KR101927553B1 - Use of nitrooxy organic molecules in feed for reducing methane emission in ruminants, and/or to improve ruminant performance - Google Patents
Use of nitrooxy organic molecules in feed for reducing methane emission in ruminants, and/or to improve ruminant performance Download PDFInfo
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- KR101927553B1 KR101927553B1 KR1020137015688A KR20137015688A KR101927553B1 KR 101927553 B1 KR101927553 B1 KR 101927553B1 KR 1020137015688 A KR1020137015688 A KR 1020137015688A KR 20137015688 A KR20137015688 A KR 20137015688A KR 101927553 B1 KR101927553 B1 KR 101927553B1
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- Prior art keywords
- nitrooxy
- formula
- ranges
- cyclic
- feed
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Classifications
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- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/24—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P60/00—Technologies relating to agriculture, livestock or agroalimentary industries
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Abstract
본 발명은, 사료와 함께 동물에게 투여되는 활성 화합물로서, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자 또는 이의 염을 사용하여, 반추동물의 소화 활동으로부터 발생되는 메탄의 생산을 감소시키고/감소시키거나 반추동물의 발육을 개선시키는 방법에 관한 것이다. 본 발명은 또한, 사료 및 사료 첨가제, 예컨대 예비배합물, 농축물 및 완전 배합 사료(TMR) 또는 볼러스의 형태의 상기 화합물의 용도에 관한 것이다.The present invention relates to an active compound which is administered to an animal together with a feed comprising at least one organic molecule or salt thereof substituted with at least one nitrooxy group at any position to reduce the production of methane from the digestive activity of the ruminant ≪ / RTI > and / or improving the development of ruminants. The present invention also relates to the use of such compounds in the form of feed and feed additives such as pre-formulations, concentrates and whole feeds (TMR) or bolus.
Description
본 발명은 반추동물의 소화 활동으로부터 발생되는 메탄의 생산을 감소시키고/감소시키거나 반추동물의 발육(performance)을 개선시키기 위한, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자의 용도에 관한 것이다.The present invention relates to the use of one or more organic molecules substituted at one or more nitrooxy groups at any position to reduce the production of methane resulting from the digestive activity of ruminants or to improve the performance of ruminants .
본 발명은 또한 상기 언급된 분자를 포함하는 동물 사료 또는 동물 사료 조성물 및 사료 첨가제에 관한 것이다. 사료 또는 사료 조성물이라는 용어는 동물이 섭취하기에 적합하거나 동물이 섭취하도록 의도된 임의의 화합물, 제제, 혼합물 또는 조성물을 의미한다.The present invention also relates to animal feed or animal feed compositions and feed additives comprising the above-mentioned molecules. The term feed or feed composition means any compound, preparation, mixture or composition suitable for ingestion by an animal or intended for consumption by an animal.
본원에서, 반추동물은, 식물계 식품을 반추위(rumen)로 공지된 동물의 첫번째 위내에서 초기에 연화시키고 이어서 되새김질 거리(cud)로 공지된 반(semi)-소화된 덩어리를 역류시키고 이를 다시 씹음으로써 소화시키는 우제류(Artiodactyla) 목의 포유동물이다. 식물 물질을 추가로 파쇄하고 소화를 자극하기 위해 되새김질 거리를 다시 씹는 과정은 "되새김질(ruminating)"이라고 지칭한다.Herein, the ruminant can be obtained by initially softening the plant food in the first stomach of a rumen known animal and then refluxing the known semi-digested lump with a cuddle (cud) and chewing it again It is a mammal of the Digestive Ostrich ( Artiodactyla ) neck. The process of re-chewing the rumpling distance to further disrupt plant material and stimulate digestion is referred to as "ruminating ".
반추위 발효는 몇가지 단점이 있다. 혐기성 발효의 자연적 결과로서 메탄이 생산되고, 이는 숙주 동물에 대한 에너지 손실을 나타낸다. 탄수화물은 전형적인 젖소 배급량 중 건조 물질의 70 내지 80%를 구성하지만, 위장관으로부터 이러한 탄수화물의 흡수는 일반적으로 매우 제한된다. 이런 이유는 반추위에서의 탄수화물의 광범위 발효가 주요 생성물로서 아세테이트, 프로피오네이트 및 부티레이트를 생성하기 때문이다. 이들 생성물은 소위 휘발성 지방산(VFA: volatile fatty acid)의 일부이다.Rumen fermentation has several disadvantages. Methane is produced as a natural consequence of anaerobic fermentation, which represents an energy loss to the host animal. Although carbohydrates make up 70-80% of the dry matter in a typical cow ration, the absorption of these carbohydrates from the gastrointestinal tract is generally very limited. This is because the broad fermentation of carbohydrates in the rumen produces acetate, propionate and butyrate as the major products. These products are part of the so-called volatile fatty acid (VFA).
에너지 손실 이외에, 메탄은 또한 온실 가스이고, 이는 CO2에 비해 수 배 더 강력하다. 대기압에서 이의 농도는 지난 세기에 걸쳐 2배가 되었고 놀랄 만큼 증가하고 있다. 반추동물은 생물 유래 메탄 형성에 대한 주요 기여자이고, 반추동물로부터의 메탄 형성의 방지가 대기의 메탄 농도를 안정화시킬 것으로 추정된다.In addition to energy losses, methane is also a greenhouse gas, which is several times more powerful than CO 2 . Its concentration at atmospheric pressure has doubled over the last century and is growing remarkably. Ruminants are a major contributor to biogenic methane formation, and prevention of methane formation from ruminants is presumed to stabilize atmospheric methane concentrations.
더욱이, 2009년 코펜하겐 기후 회담에 따른 교토 의정서(Kyoto protocol)의 평가에 따라 다중-기체 전략의 일부로서 메탄 방출을 감소시킴이 점점 우선시되고 있다. 메탄 형성을 감소시키기 위해 현재 사용되는 가장 효과적인 첨가제는 메탄생성원에게 수소(H2)를 제공하는 미생물의 증식을 약화시키는 항생제를 함유한다(자우어(Sauer) 등, 동물 과학 미국 협회(American Society of Animal Science); 76: 906-914). 그러나, 메탄의 형성에 미치는 항생제의 영향은, 짧은 기간(2 내지 3주)내 의도한 효과를 완전히 무색하게 하는 미생물상의 신속한 적응력 및/또는 내성의 진행, 및 유럽에서의 비치료 용도로서의 항생제 사용의 금지 때문에, 몇몇 단점을 갖는다.Moreover, it is increasingly preferred to reduce methane emissions as part of a multi-gas strategy, in accordance with the Kyoto Protocol's assessment of the 2009 Copenhagen climate conference. The most effective additives currently used to reduce methane formation contain antibiotics that weaken the proliferation of microorganisms that provide hydrogen (H 2 ) to methanogenic sources (Sauer et al., American Society of Animal Science Animal Science; 76: 906-914). However, the effect of antibiotics on the formation of methane may be due to rapid adaptability and / or progression of resistance to microorganisms that completely neutralize the intended effect in a short period of time (2 to 3 weeks), and the use of antibiotics Because of the prohibition of.
시험관내 반추위 모의 모델을 사용하여 시험될 경우 메탄 방출의 감소를 유도하는 비항생제성 생성물(담즙산 유도체)이 최근에 공개되었다(WO 2010072584). 그러나, 메탄 방출의 적절한 감소를 나타내기 위해 필요한 양은 반추동물 사료 산업 비용 제약과 양립하지 않는다.Non-antibiotic products (bile acid derivatives) have been recently disclosed (WO 2010072584) that, when tested using an in vitro ruminal model, lead to a reduction in methane release. However, the amount required to demonstrate a reasonable reduction in methane emissions is incompatible with the ruminant feed industry cost constraints.
또한, 다수의 천연 식물 추출물(마늘(WO 제2009150264호), 유카(yucca), 계피, 루바브(rhubarb) 등)이 시험관내 실험에 기초하여 반추동물의 메탄 방출을 감소시키기 위한 강력한 해결책으로서 과학 문헌에 기재되었다. 그러나, 이들은 생체내 시험시 부작용(우유 중의 잔여물), 효능 부족, 또는 충분한 메탄 감소를 얻기 위해 동물에 공급되어야하는 상당히 많은 양의 첨가제 때문에 어느 것도 상업화되지 못하였다.In addition, a number of natural plant extracts, including garlic (WO 200915264), yucca, cinnamon, rhubarb, etc., have been used as a powerful solution to reduce methane emissions in ruminants based on in vitro experiments Lt; / RTI > However, they have not been commercialized because of the adverse effects (in the milk), inadequate efficacy, or a significant amount of additives that must be supplied to the animal to obtain sufficient methane reduction in vivo testing.
이러한 상황에서, 여전히 메탄 형성을 감소시키면서도 신뢰성 있고 일반적으로 허용되는 실행에 부합되지만 의학적 성질을 갖지 않는 신규한 물질을 개발할 필요가 있다. 메탄 방출을 감소시키는것 이외에, 이러한 물질은 또한 사료 전환율을 개선시키고, 사료 섭취량을 감소시키며, 체중 증가를 개선시키고 및/또는 도체(carcass), 또는 우유 수율을 개선시킴으로써 반추동물의 발육을 개선시키는데 기여할 수 있다.In this situation, there is still a need to develop new materials that meet the reliable and generally acceptable practice while still reducing methane formation, but which do not have medical properties. In addition to reducing methane emissions, these materials also improve ruminant development by improving feed conversion rates, reducing feed intake, improving weight gain, and / or improving carcass or milk yield You can contribute.
본 발명자들은 놀랍게도 이후 본원에 명시된 화합물이 숙주 동물에게 해로운 방식으로 미생물 발효에 영향을 주지 않으면서도 메탄의 형성을 본질적으로 감소시키기 위해 동물 사료에 사용하기에 큰 잠재력이 있음을 발견하였다. 게다가, 본 발명의 화합물은 또한 사료 전환율, 사료 섭취량, 체중 증가, 도체 수율, 또는 우유 수율에 의해 측정시 전체 동물 발육에 관련된 큰 이점을 갖는다. 상기 화합물은 또한 선행 기술에 기재된 화합물에 비해 더 안정하고, 동물 및 인간에 대해 더 안전하며, 지속적인 메탄 감소 효과를 유도하고, 식미(palatability)에 영향을 주지 않고, 동물 영양 산업 등과 상용성인 비용으로 산업적 규모로 생산될 수 있고, 보충되는 동물의 우유 또는 고기에 임의의 대사 산물의 축적을 일으키지 않고, 반추위에서 아주 적은 농도로 활성이다.The present inventors have surprisingly found that the compounds herein described have great potential for use in animal feed to substantially reduce the formation of methane without affecting microbial fermentation in a manner harmful to host animals. In addition, the compounds of the present invention also have significant advantages associated with whole animal development when measured by feed conversion, feed intake, body weight gain, conductor yield, or milk yield. The compounds are also more stable than the compounds described in the prior art and are safer for animals and humans, induce sustained methane reduction effects, have no effect on palatability, It can be produced on an industrial scale and is active at very low concentrations in the rumen without causing accumulation of any metabolites in the milk or meat of the supplemented animal.
특히, 본 발명자들은 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자를 반추동물에 먹이는 것이 총 VFA 생산에 부정적으로 영향을 주지 않으면서 반추동물의 소화 활동으로부터 발생되는 메탄의 생성을 감소시키고/감소시키거나 반추동물의 발육을 개선시키는데 매우 효과적인 것을 관찰하였다. 또한, 본 발명자들은 니트로옥시기가 유사한 물리화학적 특성의 다른 화학기로 대체될 경우, 메탄 생성의 기술적 효과가 사라짐을 관찰함으로써 니트로옥기기가 본 발명의 메탄 감소 효과에 대한 핵심임을 입증하였다.In particular, the present inventors have found that feeding ruminants with one or more organic molecules substituted with one or more nitrooxy groups at any position does not adversely affect total VFA production, thereby reducing the production of methane from ruminant digestive activity ≪ / RTI > and / or to improve the development of ruminants. In addition, the present inventors have demonstrated that when the nitrooxy groups are replaced with other chemical groups of similar physicochemical properties, the technological effects of methane production are lost, thereby demonstrating that the nitrooxime is the key to the methane reduction effect of the present invention.
국제 특허 출원 PCT/EP2010/069338로부터 니트로옥시-카르복실산 유도체가 시험관내 및 생체내 반추위 메탄생성의 강한 억제제임이 공지되었다. 그러므로 이들 분자는 본 발명에서는 특히 제외한다.From international patent application PCT / EP2010 / 069338 it is known that nitrooxy-carboxylic acid derivatives are potent inhibitors of in vitro and in vivo rumen methane production. These molecules are therefore excluded in the present invention.
따라서 본 발명은, 반추동물의 소화 활동으로부터 발생되는 메탄의 생성을 감소시키고/감소시키거나 반추동물의 발육을 개선시키기 위한 동물 사료중의 활성 화합물로서의, 하기 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자 또는 이의 염의 용도를 제공한다.Accordingly, the present invention relates to a method for reducing or reducing the production of methane from ruminant digestion activity, or as an active compound in an animal feed for improving the development of ruminants, At least one organic molecule or at least one salt thereof substituted with at least one nitrooxy group.
또한 본 발명은, 하기 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 유기 분자 또는 이의 염 하나 이상을 충분량으로 동물에게 경구 투여함을 포함하는, 반추동물의 소화 활동으로부터 발생되는 메탄의 생성을 감소시키고/감소시키거나 반추동물의 발육을 개선시키기 위한 방법을 제공한다. 경구 투여는 간단한 먹이를 주거나 또는 볼러스(bolus)의 수동(manual) 투여로 이해되어야한다.The present invention also relates to a method for the treatment of rheumatoid arthritis resulting from the digestive activity of a ruminant, comprising orally administering to the animal an effective amount of one or more organic molecules or salts thereof substituted with at least one nitrooxy group at any position, To reduce the production of methane and / or to improve the development of ruminants. Oral administration should be understood as a simple feeding or manual administration of bolus.
본 발명의 모든 실시양태에서, 임의의 위치에 하나 이상의 니트로옥기기가 치환된 유기 분자 또는 이의 염은 하기 화학식 I의 화합물로 정의된다:In all embodiments of the present invention, an organic molecule or a salt thereof, wherein at least one nitroso-imide is substituted at any position, is defined as a compound of formula (I)
I I
상기 식에서,In this formula,
Y는 CaHbOdNeSg의 조성의 유기분자로서, 이때 a는 1 내지 25, 바람직하게는 1 내지 10 범위이며, b는 2 내지 51, 바람직하게는 2 내지 21 범위이며, d는 0 내지 8, 바람직하게는 0 내지 6 범위이며, e는 0 내지 5, 바람직하게는 0 내지 3 범위이며, g는 0 내지 3, 바람직하게는 0 내지 1 범위이되,Y is an organic molecule having a composition of C a H b O d N e S g where a ranges from 1 to 25, preferably from 1 to 10, and b ranges from 2 to 51, preferably from 2 to 21, d ranges from 0 to 8, preferably from 0 to 6, e ranges from 0 to 5, preferably from 0 to 3, g is from 0 to 3, preferably from 0 to 1,
이때, 하기 화학식 II로 정의되는 니트로옥시 알칸산 및/또는 이의 유도체는 제외된다:At this time, the nitrooxyalkanoic acids and / or derivatives thereof defined by the following formula (II) are excluded:
II II
상기 식에서,In this formula,
u는 0 내지 23 범위이고, 이때 u ≠ 0이면, 탄소 쇄는, 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 선형, 환형, 또는 분지된 선형 또는 환형 지방족 탄소 쇄이며,u ranges from 0 to 23, where u ≠ 0, the carbon chain is a linear, cyclic, or branched linear or cyclic aliphatic carbon chain, which may be singly or multiply unsaturated and in any isomeric form,
Z는 독립적으로, O, NH 또는 N-R3이고, 이때 R1 ≠ H이면, Z-R1-은 에스터 또는 2차 아마이드 유도체를 나타내며,Z is independently O, NH or N-R3, wherein when R1 is not equal to H then Z-R1- represents an ester or secondary amide derivative,
R1은 독립적으로, 수소 또는 1 내지 10개 탄소 원자를 포함하는 알킬기 또는 알케닐기의 포화된 선형, 환형 또는 분지형 쇄이며,R1 is independently a saturated linear, cyclic or branched chain of hydrogen or an alkyl or alkenyl group comprising from 1 to 10 carbon atoms,
R2는 독립적으로, 수소 또는 1 내지 23개 탄소 원자를 포함하는 알킬기 또는 알케닐기의 포화된 선형 또는 분지형 쇄이며,R2 is independently hydrogen or a saturated linear or branched chain of an alkyl or alkenyl group containing from 1 to 23 carbon atoms,
R3은 독립적으로, 수소 또는 1 내지 10개 탄소 원자를 포함하는 알킬기 또는 알케닐기의 포화된 선형, 환형 또는 분지형 쇄이다.R3 is independently hydrogen or a saturated linear, cyclic or branched chain of an alkyl or alkenyl group comprising from 1 to 10 carbon atoms.
다른 실시양태에서, 본 발명에 따른 바람직한 화학식 I의 화합물은, a가 1 내지 10, 바람직하게는 3 내지 8 범위인 화합물이다.In another embodiment, preferred compounds of formula I according to the present invention are those wherein a is in the range of 1 to 10, preferably 3 to 8.
다른 실시양태에서, 본 발명에 따른 바람직한 화학식 I의화합물은 화학식 III의 화합물이다:In another embodiment, preferred compounds of formula I according to the present invention are compounds of formula III:
III III
상기 식에서,In this formula,
n은 0 내지 12 범위이며, 바람직하게는 0 내지 6 범위이며, 이때 n ≠ 0이면, 탄소 쇄는, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시기로 치환될 수 있는 선형, 환형 또는 분지형 지방족 탄소 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 알케닐 또는 알키닐 탄소 쇄이며,n ranges from 0 to 12 and preferably ranges from 0 to 6, where n ≠ 0, the carbon chain is unsubstituted or substituted with up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkyl- A linear, cyclic or branched aliphatic carbon chain which may be substituted with an amino- or nitrooxy group, or an alkenyl or alkynyl carbon chain which may be mono- or polyunsaturated and in any isomeric form,
R4는 독립적으로, 수소 또는 1 내지 12개, 바람직하게는 1 내지 6개의 탄소 원자를 포함하는 알킬기 또는 알케닐기의 포화된 선형, 환형 또는 분지형 쇄이며,R4 is independently a saturated linear, cyclic or branched chain of an alkyl or alkenyl group comprising hydrogen or from 1 to 12, preferably from 1 to 6 carbon atoms,
X는 수소, R5, R5≡N, -OR5, -OCOR5, -NR5R6, -ONO2, -COOR5, -CONR5R6, -NHSO2R5, 또는 -SO2NHR5이며,X is hydrogen, R5, R5≡N, -OR5, -OCOR5 , -NR5R6, -ONO 2, -COOR5, -CONR5R6, -NHSO 2 R5, or -SO 2 NHR5,
R5 및 R6은 독립적으로, 수소, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 치환된 C1 내지 C12의 선형, 분지형 또는 환형 알킬 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 알케닐 또는 알키닐 탄소 쇄이다.R5 and R6 are independently selected from the group consisting of hydrogen, C1 to C12 linear, branched or cyclic, unsubstituted or substituted with up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups Alkyl chain, or an alkenyl or alkynyl carbon chain which may be mono- or polyunsaturated and in any isomeric form.
본 발명의 모든 실시양태에서, 화학식 I의 화합물 및 화학식 III의 화합물이 임의의 이성체 형태일 수 있음이 이해되어야 한다.In all embodiments of the present invention it is to be understood that the compounds of formula I and the compounds of formula III may be in any isomeric form.
화학식 III의 화합물의 상기 정의에서, n > 2인 경우, 탄소 쇄는 탄소 쇄에 따른 임의의 위치에서 선형이거나 분지형일 수 있는 것으로 이해되어야 한다. 또한, 탄소 쇄는 탄소 쇄를 따라 상이한 위치에서 다중 분지에 의해 분지화될 수 있다. 게다가, n > 3인 경우, 지방족 탄소 쇄는 환형 잔기를 형성할 수 있다. 이러한 환형 잔기는 니트로옥시 잔기를 임의의 위치(2, 3, 4)에 가지며 또한 임의의 지방족 기에 의해 다수의 위치에서 분지화될 수 있다. 분지화된 지방족 기는 바람직하게는, 메틸, 에틸 또는 프로필이다. 또한 탄소 쇄는 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 추가로 치환될 수 있다.In the above definition of the compound of formula (III), it is to be understood that when n > 2, the carbon chain may be linear or branched at any position along the carbon chain. In addition, the carbon chain may be branched by multiple branches at different positions along the carbon chain. Furthermore, when n > 3, the aliphatic carbon chain may form a cyclic moiety. These cyclic moieties may have a nitrooxy moiety at any position (2, 3, 4) and may also be branched at multiple positions by any aliphatic group. The branched aliphatic group is preferably methyl, ethyl or propyl. The carbon chain may additionally be substituted with up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups.
화학식 III의 유도체의 상기 정의에서, 바람직한 알킬 기는 메틸, 에틸, 프로필, 아이소프로필, 부틸, 2급 부틸, 아이소부틸, 펜틸, 네오펜틸, 헥실, 사이클로헥실, 및 2-에틸-헥실 및 옥틸이다. 또한, 3개 이상의 탄소 원자를 포함하는 임의의 알킬 또는 알케닐 기는 직쇄이거나, 분지되거나, 환형일 수 있다. 또한, 직쇄 또는 분지형 C2-C10-알케닐렌 기의 경우, 이는 하나 또는 (C4로부터) 그 이상의 이중 결합을 갖는 알케닐렌 기를 내포하는 것으로 이해되어야 하고, 이러한 알케닐렌 기의 예는 식 -CH=CH-, -CH=CH-CH2-, -CH=CH-(CH2)3- 및 -(CH=CH)2-의 알킬렌 기이다.In the above definitions of derivatives of formula III, preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, pentyl, neopentyl, hexyl, cyclohexyl, and 2-ethylhexyl and octyl. In addition, any alkyl or alkenyl group containing three or more carbon atoms may be straight-chain, branched, or cyclic. In addition, in the case of straight-chain or branched C 2 -C 10 -alkenylene groups, it is to be understood that this includes alkenylene groups having one or more double bonds (from C 4 ), examples of such alkenylene groups being represented by formula -CH = CH-, -CH = CH-CH 2 -, -CH = CH- (CH 2 ) 3 - and - (CH = CH) 2 -.
다른 실시양태에서, 본 발명에 따른 더 바람직한 화학식 I의 화합물은, 3-니트로옥시프로판올, 라세메이트-4-페닐부테인-1,2-다이일 다이니트레이트, 2-(하이드록시메틸)-2-(니트로옥시메틸)-1,3-프로판다이올, N-에틸-3-니트로옥시-프로피오닉 설포닐 아마이드, 5-니트로옥시-펜테인니트릴, 5-니트로옥시-펜테인, 3-니트로옥시-프로필 프로피온에이트, 1,3-비스-니트로옥시프로페인, 1,4-비스-니트로옥시뷰테인, 1,5-비스-니트로옥시펜테인, 3-니트로옥시-프로필 벤조에이트, 3-니트로옥시-프로필 헨사노에이트, 3-니트로옥시-프로필 5-니트로옥시 헥사노에이트, 벤질니트레이트, 아이소소르비드-다이니트레이트, N-[2-(니트로옥시)에틸]-3-피리딘카복사마이드, 2-니트로-5-니트로옥시메틸-퓨란, 및 비스-(2-니트로옥시에틸) 에터를 포함하는 화합물 목록(표 1에 기재됨) 및 이들의 염으로부터 선택된다.In another embodiment, the more preferred compounds of formula I according to the present invention are selected from the group consisting of 3-nitrooxypropanol, racemate-4-phenylbutane-l, 2-dylidonitrate, 2- (hydroxymethyl) N-ethyl-3-nitrooxy-propionic sulfonylamide, 5-nitrooxy-pentenenitrile, 5-nitrooxy-pentane, 3- 3-nitrooxy-propyl benzoate, 3-nitro-3-nitropropyl benzoate, 3-nitro- -Nitroxy-propylhexanoate, 3-nitrooxy-propyl 5-nitrooxyhexanoate, benzylnitrate, isosorbide-dynitrate, N- [2- (nitrooxy) ethyl] (Shown in Table 1) containing 2-nitro-5-nitroaniline, carboxamide, 2-nitro-5-nitrooxymethyl-furan, and bis- And salts thereof.
다른 실시양태에서, 메탄을 감소하는 이들의 효과의 세기에 기초하여 더욱더 바람직한 화학식 III의 화합물은, 3-니트로옥시프로판올, 5-니트로옥시-펜테인니트릴, 5-니트로옥시-펜테인, 3-니트로옥시-프로필 프로피오네이트, 1,3-비스-니트로옥시프로페인, 1,4-비스-니트로옥시뷰테인, 1,5-비스-니트로옥시펜테인, 3-니트로옥시-프로필 벤조에이트, 3-니트로옥시-프로필 헥사노에이트, 3-니트로옥시-프로필 5-니트로옥시-헥사노에이트, 아이소소르비드-다이니트레이트, N-[2-(니트로옥시)에틸]-3-피리딘카복사마이드, 및 비스-(2-니트로옥시에틸) 에터를 포함하는 화합물 목록(표 2에 기재됨) 및 이들의 염으로부터 선택된다.In another embodiment, even more preferred compounds of formula III based on the intensity of their effect of reducing methane are 3-nitrooxypropanol, 5-nitrooxy-pentenenitrile, 5-nitrooxy-pentane, 3- Nitroxy-propyl propionate, 1,3-bis-nitrooxypropane, 1,4-bis-nitrooxybutane, 1,5-bis-nitrooxypentane, 3-nitrooxy- Nitroso-propyl hexanoate, 3-nitrooxy-propyl 5-nitrooxy-hexanoate, isosorbide-dinitrate, N- [2- (nitrooxy) ethyl] (Listed in Table 2) and salts thereof, including bis- (2-nitrooxyethyl) ether.
다른 실시양태에서, 메탄을 감소하는 이들의 효과의 세기 및 생산 방법에 기초하여 가장 바람직한 화학식 I의 화합물은 3-니트로옥시 프로판올과 1,3-비스-니트로옥시프로페인의 혼합물이다. 바람직하게는, 3-니트로옥시 프로판올/1,3-비스-니트로옥시프로페인의 비는 1/10 내지 1000/1 범위이며, 더욱 바람직하게는 1/5 내지 100/1 범위이며, 가장 바람직하게는 1/1 내지 10/1 범위이다.In another embodiment, the most preferred compound of formula I is a mixture of 3-nitrooxypropanol and 1,3-bis-nitrooxypropane based on the intensity of their effect and the method of production to reduce methane. Preferably, the ratio of 3-nitrooxypropanol / 1,3-bis-nitrooxypropane is in the range of 1/10 to 1000/1, more preferably in the range of 1/5 to 100/1, Is in the range of 1/1 to 10/1.
본 발명의 화합물은 또한 니트로옥시 유기 분자의 염을 포함한다. 염 제조에 바람직한 양이온은 나트륨(Na+), 칼륨(K+), 리튬(Li+), 마그네슘(Mg2 +), 칼슘(Ca2 +), 바륨(Ba2 +), 스트론튬(Sr2 +), 및 암모늄(NH4 +)으로 구성된 군으로부터 선택될 수 있다. 염은 또한 알칼리 금속 또는 알칼리 토금속으로부터 제조될 수 있다.The compounds of the present invention also include salts of nitrooxy organic molecules. The preferred cation in the manufacture salts are sodium (Na +), potassium (K +), lithium (Li +), magnesium (Mg 2 +), calcium (Ca 2 +), barium (Ba 2 +), strontium (Sr 2 + ) to, and ammonium (NH 4 +) may be selected from the group consisting of. Salts may also be prepared from alkali metals or alkaline earth metals.
본 발명의 화합물은 원칙적으로 니트로옥시 유기 분자에 대해 자체 공지된 합성 방법에 따라 또는 실시예에 기재된 방법에 기초하여 제조될 수 있다.The compounds of the invention can in principle be prepared according to known synthetic methods for nitrooxy organic molecules or on the basis of the methods described in the examples.
모든 경우, 생성물(화학식 I의 화합물)을 정제하기 위한 적절한 방법은 당해 분야의 숙련자에 의해, 즉 칼럼 크로마토그래피에 의해 선택될 수 있거나, 화학식 I의 화합물은 자체 공지된 방법에 의해, 예를 들어 용매, 예컨대 다이에틸-에터 또는 에틸 아세테이트를 첨가하여 반응 혼합물로부터 조질 생성물의 분리를 유도하고, 수집된 조질 생성물을 Na2SO4 상에서 건조시킴으로써 단리되고 정제될 수 있다.In all cases, suitable methods for purifying the product (compounds of formula (I)) may be selected by those skilled in the art, i. E. By column chromatography, or the compounds of formula I may be prepared by methods known per se, A solvent such as diethyl ether or ethyl acetate may be added to induce the separation of the crude product from the reaction mixture and the collected crude product may be isolated and purified by drying over Na 2 SO 4 .
반추동물에 의한 메탄 방출은 당해 분야에 공지된 방법에 의해 대사 챔버(metabolic chamber)에서 개별 동물에 대해 쉽게 측정될 수 있다(Grainger et al., 2007 J. Dairy Science; 90: 2755-2766). 게다가, 이는 또한 레이저 빔을 사용하는 이머징 기술(emerging technology)에 의해 외양간 수준에서 평가될 수 있다(McGinn et al., 2009, Journal of Environmental Quality; 38: 1796-1802). 달리, 낙농 반추동물에 의해 생산된 메탄은 또한 WO 제2009/156453호에 따라서 우유 중 VFA 프로파일의 측정에 의해 평가될 수 있다.The release of methane by ruminants can be easily measured for individual animals in a metabolic chamber by methods known in the art (Grainger et al., 2007 J. Dairy Science; 90: 2755-2766). In addition, it can also be assessed at the barn level by emerging technology using laser beams (McGinn et al., 2009, Journal of Environmental Quality; 38: 1796-1802). Alternatively, methane produced by dairy ruminants can also be assessed by measuring the VFA profile in milk according to WO 2009/156453.
반추동물의 발육은 당해 분야에 널리 공지된 방법에 의해 평가될 수 있고, 통상적으로 사료 전환율, 사료 섭취량, 체중 증가, 도체 수율, 또는 우유 수율에 의해 특징지워진다.The development of ruminants can be assessed by methods well known in the art and is typically characterized by feed conversion, feed intake, body weight gain, conductor yield, or milk yield.
본 발명은 또한, 반추위에서의 메탄 형성과 관련하여 유사한 효과를 나타내고 다이알릴 다이설파이드, 마늘 기름(garlic oil), 알릴 아이소티오시아네이트, 데옥시콜산, 케노데옥시콜산 및 이의 유도체로 구성된 군에서 선택되는 하나 이상의 추가 활성 물질과 조합된, 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자 또는 이의 염의 용도에 관한 것이다.The present invention also relates to the use of a compound of the formula I which exhibits a similar effect with respect to the formation of methane in the rumen and which is selected from the group consisting of diallyl disulfide, garlic oil, allyl isothiocyanate, deoxycholic acid, chenodeoxycholic acid and derivatives thereof The present invention relates to the use of at least one organic molecule or salt thereof substituted with at least one nitrooxy group at any position, as defined by formula (I), in combination with one or more additional active substances selected.
본 발명에 따른 화합물과 함께 제공될 수 있는 추가의 성분은 예를 들어 효모, 정유(essential oil), 및 이온투과담체, 예컨대 모넨신(Monensin), 루멘신(Rumensin)이다.Additional components which may be provided with the compounds according to the invention are, for example, yeast, essential oils, and ion-permeable carriers such as Monensin, Rumensin.
현재 다이알릴 다이설파이드, 마늘 기름, 알릴 다이소티오시아네이트, 데옥시콜산, 케노데옥시콜산 및 이의 유도체가 사료(㎏) 당, 예를 들어 0.01 내지 500mg(ppm)의 활성 물질의 용량 범위 내에서 독립적으로 투여되는 것이 고려된다. 이들 화합물은 상업적으로 입수가능하거나, 당해 분야에 널리 공지된 공정 및 방법을 사용하여 숙련자에 의해 쉽게 제조될 수 있다.At present, the active ingredient is present in a dose range of from 0.01 to 500 mg (ppm) per kilogram of feed (kg) of diallyl disulfide, garlic oil, allyl diester thiocyanate, deoxycholic acid, Lt; / RTI > These compounds are either commercially available or can be readily prepared by those skilled in the art using processes and methods well known in the art.
본 발명에 따른 반추 포유동물은 소, 염소, 양, 기린, 미국 들소, 유럽 들소, 야크(yak), 물소, 사슴, 낙타, 알파카(alpaca), 라마, 누(wildebeest), 영양, 가지뿔영양(pronghorn), 및 닐가이 영양(nilgai)을 포함한다.The ruminant mammals according to the present invention are useful for the treatment and prevention of ruminants such as cattle, goats, sheep, giraffes, american bison, European bison, yak, buffalo, deer, camel, alpaca, llama, wildebeest, pronghorn, and nilgai. < / RTI >
본 발명의 모든 실시양태에서, 가축 소, 양 및 염소가 더 바람직한 종이다. 본 목적을 위해, 더 바람직한 종은 가축 소이다. 이 용어는 모든 종의 가축 소 및 소의 모든 생산 품종, 특히 젖소 및 육우를 포함한다.In all embodiments of the present invention, animal cattle, sheep and chlorine are the more preferred species. For this purpose, the more preferred species is livestock. This term covers all production varieties of cattle and cattle of all species, especially cows and beef cattle.
본 발명은 또한, 건조 물질 섭취량(㎏) 당 리터(ℓ)로 계산된 반추동물에서의 메탄 생산량이 대사 챔버에서 측정시 10% 이상 감소되는, 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자 또는 이의 유도체의 용도에 관한 것이다. 바람직하게는, 메탄 감소는 15% 이상, 더 바람직하게는 20% 이상, 더욱더 바람직하게는 25% 이상, 가장 바람직하게는 30% 이상이다. 우유 중 VFA 프로파일에 대한 메탄 생산의 상관관계를 지어주는 낙농 반추동물을 위한 레이저 빔의 사용 등 다른 메탄 방출 측정법이 또한 사용될 수 있다.The present invention also relates to a process for the preparation of a compound of formula I as defined in formula I, wherein the methane production in the ruminant, calculated as liters per kilogram of dry matter (kg), is reduced by at least 10% At least one organic molecule substituted with an oxy group or a derivative thereof. Preferably, the methane reduction is at least 15%, more preferably at least 20%, even more preferably at least 25% and most preferably at least 30%. Other methane emission measurements can also be used, such as the use of laser beams for dairy ruminants to correlate methane production to VFA profiles in milk.
본 발명은 또한, 통상적인 사육 시험에서 측정시 반추동물 사료 전환율이 1% 이상 감소되는, 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자 또는 이의 유도체의 용도에 관한 것이다. 바람직하게는, 사료 전환율은 2% 이상, 더 바람직하게는 2.5% 이상, 더욱더 바람직하게는 3% 이상, 가장 바람직하게는 3.5% 이상 감소된다.The present invention also relates to the use of one or more organic molecules or derivatives thereof wherein at least one nitrooxy group is substituted at any position, as defined by formula I, wherein the ratio of ruminant feed conversion is reduced by at least 1% as measured in a conventional breeding test . Preferably, the feed conversion is reduced by at least 2%, more preferably at least 2.5%, even more preferably at least 3%, most preferably at least 3.5%.
본 발명은 또한, 반추동물에게 투여되는 화학식 I로 정의된 하나 이상의 활성 화합물의 양이 사료(㎏) 당 1㎎ 내지 10g, 바람직하게는 사료(㎏) 당 10㎎ 내지 1g, 더 바람직하게는 사료(㎏) 당 50㎎ 내지 500㎎인, 화학식 I로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기분자 또는 이의 유도체의 용도에 관한 것이다. 그러나, 동물 사료에 사용하는 경우, 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 유기 분자 또는 이의 염은 순수할 필요가 없으며, 예를 들어 다른 화합물 및 유도체를 포함할 수 있다.The present invention also relates to a method for the treatment of rheumatoid arthritis comprising administering to a ruminant an amount of at least one active compound as defined by formula I of from 1 mg to 10 g, preferably from 10 mg to 1 g per kg of feed, (50 mg to 500 mg per kilogram) of at least one organic molecule or derivative thereof substituted at one or more nitrooxy groups at any position, as defined by formula (I). However, when used in animal feeds, the organic molecules, or salts thereof, substituted with at least one nitrooxy group at any position, defined by formula (I), need not be pure and may include, for example, other compounds and derivatives .
상기 기재된 바와 같이, 본 발명의 화합물은 반추동물을 위한 사료 첨가제 및 동물 사료 조성물을 위한 화합물로서 유용하고, 따라서 이러한 사료에서 동물의 소화관에서의 메탄 형성을 감소시키고/감소시키거나 반추동물의 발육을 개선시키는 활성 성분으로서 유용하다.As described above, the compounds of the present invention are useful as feed additives for ruminants and as compounds for animal feed compositions, and as such reduce the formation of methane in the digestive tract of animals in such feeds or reduce the development of ruminants And is useful as an active ingredient for improving.
반추동물의 사료를 위한 이러한 성분들로서의 이들의 용도를 실현하기 위해, 상기 화합물은 사료 제형 및 가공 분야에서 자체 공지된 방법에 의해 사료에 혼입될 수 있다.To realize their use as such ingredients for ruminant feed, the compounds may be incorporated into the feed by methods known in the art of feed formulation and processing.
따라서, 본 발명의 추가의 양태는 제형, 즉 본원에 상기 정의된 화합물을 함유하는 사료 첨가제 및 동물 사료 조성물이다. 또한 본 발명은 화학식 I의 하나 이상의 화합물 또는 이의 염을 포함하는 사료 조성물 또는 사료 첨가제에 관한 것이다. 바람직하게는, 사료 조성물 또는 사료 첨가제는 반추동물용 기초 배합물이다. 바람직한 실시양태에서, 상기 조성물은 무기물 예비배합물, 비타민 및 무기물을 포함하는 비타민 예비배합물, 또는 볼러스(bolus)이다.Accordingly, a further aspect of the present invention is a formulation, i.e. a feed additive and an animal feed composition containing a compound as defined hereinabove. The invention also relates to a feed composition or feed additive comprising at least one compound of formula I or a salt thereof. Preferably, the feed composition or feed additive is a rudimentary animal blend. In a preferred embodiment, the composition is a preliminary combination of minerals, a vitamin pre-combination comprising vitamins and minerals, or a bolus.
사료 섭취에 의해 동물에게 제공되는 본 발명에 따른 화합물의 정상적인 1일 투여량은 동물의 종류 및 그의 상태에 따라 달라진다. 정상적으로, 이러한 투여량은 사료(㎏) 당 약 1㎎ 내지 약 10g, 바람직하게는 약 10㎎ 내지 약 1g, 더 바람직하게는, 50㎎ 내지 500㎎의 화합물의 범위여야 한다.The normal daily dose of a compound according to the invention provided to the animal by feed ingestion will depend on the species of animal and its condition. Normally, such dosage should range from about 1 mg to about 10 g, preferably from about 10 mg to about 1 g, more preferably from 50 mg to 500 mg of compound per kilogram of feed (kg).
화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 하나 이상의 유기 분자 또는 이의 유도체는 동물 사료 조성물(식이)에 존재하는 통상의 성분들, 예컨대 탄산칼슘, 전해질, 예컨대 염화 암모늄, 단백질, 예컨대 대두박, 밀, 전분, 해바라기 깻묵, 옥수수, 육골분 사료, 아미노산, 동물 지방, 비타민 및 미량 무기물과 함께 사용될 수 있다.The one or more organic molecules or derivatives thereof, wherein at least one of the nitrooxy groups is substituted at any position, defined by the formula (I), may contain conventional components present in an animal feed composition (diet) such as calcium carbonate, an electrolyte such as ammonium chloride, Such as soybean meal, wheat, starch, sunflower oil, corn, bone meal, amino acids, animal fats, vitamins and trace minerals.
본 발명의 조성물의 특정한 예는 다음과 같다:Specific examples of the composition of the present invention are as follows:
- (a) 표 1로부터 선택된 하나 이상의 화합물, (b) 하나 이상의 지용성 비타민, (c) 하나 이상의 수용성 비타민, (d) 하나 이상의 미량 무기물, 및/또는 (e) 하나 이상의 주요 무기물을 포함하는 동물 사료 첨가제;(a) one or more compounds selected from Table 1, (b) one or more fat soluble vitamins, (c) one or more water soluble vitamins, (d) one or more trace minerals, and / Feed additive;
- 표 1로부터 선택된 하나 이상의 화합물 및 사료 1kg당 50 내지 800g의 조질의 단백질 성분을 포함하는 동물 사료 조성물.- an animal feed composition comprising at least one compound selected from Table 1 and from 50 to 800 g of a crude protein component per kg of feed.
그러므로, 바람직한 실시양태에서, 본 발명은 반추동물 사료 조성물 또는 사료 첨가제에 관한 것이다.Therefore, in a preferred embodiment, the present invention relates to a ruminant feed composition or feed additive.
소위 예비배합물(premix)이 본 발명의 동물 사료 첨가제의 예이다. 예비배합물은 바람직하게는 하나 이상의 미세 성분과 희석제 및/또는 담체의 균일한 혼합물을 나타낸다. 예비배합물은 더 큰 배합물 중 미세 성분의 균일한 분산을 용이하게하기 위해 사용된다.A so-called premix is an example of an animal feed additive of the present invention. The preformulation preferably represents a homogeneous mixture of the diluent and / or carrier with one or more of the micronutrients. The preformulation is used to facilitate uniform dispersion of the fine components in the larger formulation.
본 발명의 활성 성분들 이외에, 본 발명의 예비배합물은 하나 이상의 지용성 비타민, 및/또는 하나 이상의 수용성 비타민, 및/또는 하나 이상의 미량 무기물, 및/또는 하나 이상의 주요 무기물을 함유한다. 달리 말하면, 본 발명의 예비배합물은 본 발명에 따른 하나 이상의 화합물을 지용성 비타민, 수용성 비타민, 미량 무기물, 및 주요 무기물로 구성된 군으로부터 선택된 하나 이상의 추가의 성분과 함께 함유한다.In addition to the active ingredients of the present invention, the preformulation of the present invention contains one or more fat soluble vitamins, and / or one or more water soluble vitamins, and / or one or more trace minerals, and / or one or more major minerals. In other words, the pre-combination of the present invention contains one or more compounds according to the invention together with one or more additional ingredients selected from the group consisting of fat-soluble vitamins, water-soluble vitamins, trace minerals, and major minerals.
주요 무기물은 별도로 사료에 첨가될 수도 있다. 따라서, 특정 실시태양에서, 예비배합물은 본 발명의 활성 구성성분을 지용성 비타민, 수용성 비타민, 및 미량 무기물로 구성된 군으로부터 선택된 하나 이상의 추가의 성분과 함께 포함한다.Major minerals may be added to the feed separately. Thus, in certain embodiments, the preformulation comprises the active ingredients of the present invention together with one or more additional ingredients selected from the group consisting of fat soluble vitamins, water soluble vitamins, and trace minerals.
하기는 이들 성분의 예에 대한 비제한적인 목록이다:The following is a non-limiting list of examples of these ingredients:
- 지용성 비타민의 예는 비타민 A, 비타민 D3, 비타민 E, 및 비타민 K, 예를 들어 비타민 K3이다.Examples of fat-soluble vitamins are vitamin A, vitamin D3, vitamin E, and vitamin K, for example vitamin K3.
- 수용성 비타민의 예는 비타민 B12, 비오틴 및 콜린, 비타민 B1, 비타민 B2, 비타민 B6, 니아신, 폴산 및 판토테네이트, 예를 들어 Ca-D-판토테네이트이다.Examples of water-soluble vitamins are vitamin B12, biotin and choline, vitamin B1, vitamin B2, vitamin B6, niacin, folic acid and pantothenate, such as Ca-D-pantothenate.
- 미량 무기물의 예는 망간, 아연, 철, 구리, 요오드, 셀레늄 및 코발트이다.Examples of trace minerals are manganese, zinc, iron, copper, iodine, selenium and cobalt.
- 주요 무기물의 예는 칼슘, 인 및 나트륨이다.Examples of major minerals are calcium, phosphorus and sodium.
반추동물, 예컨대 소를 위한 사료 조성물, 뿐만 아니라 이의 구성성분과 관련하여, 반추동물 식이는 일반적으로 쉽게 분해가능한 부분(농축물로 지칭됨) 및 섬유질이 풍부한 쉽게 분해되지 않는 부분(건초, 포리지(forage), 또는 조질 사료로 지칭됨)으로 구성된다.With respect to feed compositions for ruminants, such as cattle, as well as their constituents, ruminant diets generally comprise a readily degradable fraction (referred to as a concentrate) and a fiber-rich readily degradable fraction (hay, (referred to as forage, or crude feed).
건초는 건조된 목초, 협과(legume) 또는 전곡(whole cereal)으로 이루어 진다. 목초로는 티모시(timothy), 독보리(ryegrass), 페스큐(fescue)가 포함된다. 협과로는 클로버, 루체른(lucerne) 또는 알팔파(alfalfa), 완두콩, 콩 및 살갈퀴(vetch)가 포함된다. 전곡으로는 보리, 메이즈(maize)(옥수수), 귀리, 수수가 포함된다. 다른 포리지 작물로는 사탕수수, 케일, 유채 및 양배추가 포함된다. 또한 근채류, 예컨대 순무, 스웨덴 순무, 망그로브 열매(mangle), 포더 비트(fodder beet), 및 사탕무(사탕무 펄프 및 당밀 포함)가 반추동물 사료에 사용된다. 추가의 작물은 덩이줄기, 예컨대 감자, 카사바(cassava) 및 고구마이다. 사일리지(silage)는 섬유가 풍부한 부분(예를 들어 목초, 협과 또는 전곡으로부터)의 사일로(silo)에 저장된 형태이고, 여기서 높은 수분 함량을 갖는 물질은 제어된 혐기성 발효 과정으로 처리된다(천연 발효되거나 첨가제 처리됨).Hayes consist of dried grasses, legumes or whole cereals. Pastures include timothy, ryegrass, and fescue. Negotiations include clover, lucerne or alfalfa, peas, beans and vetch. Whole songs include barley, maize (corn), oats, and sorghum. Other forage crops include sugar cane, kale, rapeseed and cabbage. Also root vegetables such as turnip, swede turnip, mangrove, fodder beet, and sugar beet (including beet pulp and molasses) are used in ruminant feed. Additional crops are tubers, such as potato, cassava and sweet potato. Silage is a form stored in a silo of a fiber-rich portion (e.g., from grass, corn, or whole grains), where materials with high moisture content are treated by controlled anaerobic fermentation processes Additive treated).
농축물은 대부분 곡류(예컨대 맥주박 및 증류기 그레인을 포함하는 보리, 메이즈, 밀, 수수)로 구성되지만, 또한 보통 단백질이 풍부한 사료 구성성분, 예컨대 대두, 평지씨, 팜핵(palm kernel), 목화씨 및 해바라기씨를 함유한다.The concentrates are mostly composed of cereal grains (such as barley, maize, wheat, millet, including brewer and distiller grains), but also usually contain protein-rich feed ingredients such as soybean, rapeseed, palm kernel, cotton seed and sunflower It contains seeds.
소에게는 또한 완전 배합 사료(TMR: total mixed ration)가 제공되고, 이때 제공 이전에 모든 식이 성분, 예를 들어 포리지, 사일리지 및 농축물이 혼합된다.Cows are also provided with total mixed ration (TMR), where all dietary components, such as forage, silage and concentrates, are mixed before serving.
상기 언급된 바와 같이, 예비배합물은 본 발명에 따른 활성 화합물을 포함할 수 있는 사료 첨가제의 예이다. 상기 화합물은 상이한 다른 형태로 동물에게 투여될 수 있는 것으로 이해된다. 예를 들면, 상기 화합물은 또한 볼러스에 포함될 수 있는데, 이는 반추위에 위치되어 특정 기간에 걸쳐 잘 규정된 투여량으로 연속적으로 규정된 양의 활성 화합물을 방출할 것이다.As mentioned above, the preformulation is an example of a feed additive that may comprise an active compound according to the present invention. It is understood that the compounds may be administered to animals in different forms. For example, the compound may also be included in the bolus, which is located in the rumen and will release a continuously specified amount of the active compound at a well-defined dose over a specified period of time.
본 발명은 추가로 충분량의 화학식 I로 정의된, 임의의 위치에 하나 이상의 니트로옥시기가 치환된, 하나 이상의 유기 분자 또는 이의 염을 상기에 기재된 바람직한 실시양태로 경구 투여함을 포함하는, 반추동물의 소화 활동으로부터 발생되는 메탄의 생산을 감소시키고/감소시키거나 반추동물의 발육을 개선시키는 방법에 관한 것이다.The present invention further provides a method for the treatment of rheumatoid arthritis, comprising orally administering to a preferred embodiment as described above one or more organic molecules or salts thereof wherein at least one nitrooxy group is substituted at any position, To reduce / reduce the production of methane from digestive activity or to improve the development of ruminants.
게다가, 본 발명은 추가로, 화학식 I의 화합물이 다이알릴 다이설파이드, 마늘 기름, 알릴 아이소티오시아네이트, 데옥시콜산, 케노데옥시콜산 및 이의 유도체로 구성된 군으로부터 선택된 하나 이상의 추가의 활성 물질과 함께 동물에게 투여되는, 상기 기재된 방법에 관한 것이다.In addition, the invention further relates to the use of the compounds of formula I in combination with one or more further active substances selected from the group consisting of diallyl disulfide, garlic oil, allyl isothiocyanate, deoxycholic acid, chenodeoxycholic acid and derivatives thereof and ≪ / RTI > is administered to an animal together.
본 발명은 또한, 반추동물이 소, 염소, 양, 기린, 미국 들소, 유럽 들소, 야크, 물소, 사슴, 낙타, 알파카, 라마, 누, 영양, 가지뿔영양, 및 닐가이 영양으로 구성된 군으로부터 선택되고, 바람직하게는 소, 염소 및 양으로 구성된 군으로부터 선택되는, 상기 기재된 방법에 관한 것이다.The present invention also provides a method of treating rheumatoid arthritis in a mammal which comprises administering to the mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, And is preferably selected from the group consisting of cows, chlorine and an amount.
본 발명은 또한, 반추동물에게 투여되는 화학식 I로 정의되는, 하나 이상의 활성 화합물의 양이 사료(㎏) 당 약 1㎎ 내지 약 10g, 바람직하게는 사료(㎏) 당 약 10㎎ 내지 약 1g, 더 바람직하게는 사료(㎏) 당 50㎎ 내지 500㎎의 화합물인, 상기 기재된 방법에 관한 것이다.The present invention also provides a method of treating rheumatoid arthritis comprising administering to a ruminant an amount of at least one active compound, as defined by formula I, of from about 1 mg to about 10 g per kilogram of feed, preferably from about 10 mg to about 1 g per kilogram of feed, More preferably from 50 mg to 500 mg per kilogram of feed (kg).
본 발명은 또한 건조 물질 섭취량(㎏) 당 리터(ℓ)로 계산된 반추동물에서의 메탄 생산량이 대사 챔버에서 측정시 10% 이상 감소되는, 상기 기재된 방법에 관한 것이다. 바람직하게는, 메탄 생산은 15% 이상, 더 바람직하게는, 20% 이상, 더욱더 바람직하게는 25% 이상, 가장 바람직하게는 30% 이상이다. 우유 중 VFA 프로파일에 대한 메탄 생산의 상관관계를 지어주는 낙농 반추동물을 위한 레이저 빔의 사용 등 다른 메탄 방출 측정법이 또한 사용될 수 있다.The present invention also relates to the method as described above, wherein the methane production in the ruminant calculated as liters per kilogram of dry matter (kg) is reduced by at least 10% in the measurement in the metabolic chamber. Preferably, the methane production is at least 15%, more preferably at least 20%, even more preferably at least 25% and most preferably at least 30%. Other methane emission measurements can also be used, such as the use of laser beams for dairy ruminants to correlate methane production to VFA profiles in milk.
본 발명은 또한, 반추동물 사료 전환율이 통상의 발육 시험에서 측정시 1% 이상 감소되는, 상기 기재된 방법에 관한 것이다. 바람직하게는, 사료 전환율은 2% 이상, 더 바람직하게는 2.5% 이상, 더욱더 바람직하게는 3% 이상, 가장 바람직하게는 3.5% 이상 감소된다.The present invention also relates to a method as described above, wherein the ruminant feed conversion is reduced by at least 1% as measured in a conventional developmental test. Preferably, the feed conversion is reduced by at least 2%, more preferably at least 2.5%, even more preferably at least 3%, most preferably at least 3.5%.
본 발명은 하기 실시예에 의해 추가로 설명되고, 이는 본 발명의 범주를 제한하는 것으로 해석되지 않아야 한다.The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
실시예Example
실시예 1: 메탄 생산을 위한 시험관내 시험 Example 1 : In-vitro testing for methane production
"호헨하임 포리지 값 시험(HFT: Hohenheim Forage value Test)"의 변형된 형태를 사용하여 이러한 시험관내 시스템에 의해 모의된 반추위 기능에 대한 특정 화합물의 효과를 시험하였다.The modified form of the " Hohenheim Forage value Test "(HFT) was used to test the effect of a particular compound on the ruminal function simulated by this in vitro system.
원리:principle:
사료를 반추위액과 완충액들의 적절한 혼합물의 조성물과 함께 주사기내로 제공한다. 용액을 39℃에서 배양한다. 8시간 후, 생산된 메탄의 양(및 조성)을 측정하고 전환을 위해 배합물 내로 넣는다.The feed is fed into a syringe with the composition of a suitable mixture of ruminant juice and buffers. The solution is incubated at 39 占 폚. After 8 hours, the amount (and composition) of methane produced is measured and placed into the formulation for conversion.
시약:reagent:
주요 원소 용액: Main element solution :
- 6.2g 인산 이수소 칼륨(KH2PO4)- 6.2 g Potassium dihydrogenphosphate (KH 2 PO 4 )
- 0.6g 황산 마그네슘 7수화물(MgSO4 * 7H2O)- 0.6 g Magnesium sulfate heptahydrate (MgSO 4 * 7H 2 O)
- 9㎖ 농축 인산(1몰/ℓ)- 9 ml concentrated phosphoric acid (1 mol / l)
- 1ℓ로 증류수에 용해됨(pH 약 1.6)- 1 liter dissolved in distilled water (pH about 1.6)
완충 용액: Buffer solution :
- 35.0g 탄산 수소 나트륨(NaHCO3)- 35.0 g Sodium hydrogencarbonate (NaHCO 3 )
- 4.0g 탄산 수소 암모늄((NH4)HCO3)- 4.0 g Ammonium hydrogen carbonate ((NH 4 ) HCO 3 )
- 1ℓ로 증류수에 용해됨- dissolved in distilled water in 1 L
미량 원소 용액: Trace element solution :
- 13.2g 염화칼슘 이수화물(CaCl2 * 2H2O)- 13.2 g Calcium chloride dihydrate (CaCl 2 * 2H 2 O)
- 10.0g 염화 망간(II) 4수화물(MnCl2 * 4H2O)- 10.0 g Manganese (II) chloride tetrahydrate (MnCl 2 * 4H 2 O)
- 1.0g 염화 코발트(II) 6수화물(CoCl2 * 6H2O)- 1.0 g Cobalt (II) hexahydrate (CoCl 2 * 6H 2 O)
- 8.0g 염화 철(III)(FeCl3 * 6H2O)- 8.0 g Iron (III) chloride (FeCl 3 * 6H 2 O)
- 100㎖로 증류수에 용해됨- 100 ml dissolved in distilled water
나트륨 염 용액: Sodium salt solution :
- 100㎎ 나트륨 염- 100 mg sodium salt
- 100㎖로 증류수에 용해됨- 100 ml dissolved in distilled water
환원 용액: Reducing solution :
- 우선 3㎖의 수산화 나트륨(c = 1몰/ℓ)을, 이어서 427.5㎎의 황산 나트륨 수화물(Na2S * H2O)을 71.25㎖ H2O에 첨가한다.First, 3 ml of sodium hydroxide (c = 1 mol / l) is added followed by 427.5 mg of sodium sulfate hydrate (Na 2 S * H 2 O) to 71.25 ml of H 2 O.
- 용액은 이를 배지 용액에 첨가하기 직전에 제조되어야 한다.- The solution should be prepared just before adding it to the medium solution.
절차:step:
샘플 칭량: Sample weighing :
사료 물질(일반적으로 TMR(44% 농축물, 6% 건초, 37% 메이즈 사일리지 및 13% 목초 사일리지))을 1mm로 체질하고 64개의 주사기로 정확하게 칭량한다. 이들 주사기 중 4개는 기질 대조군이고, 이는 시험된 화합물의 효과가 없는 기체 생산을 나타낸다. 4개의 다른 주사기는 양성 대조군이고, 여기에는 브로모에테인 설포네이트가 0.1mM로 첨가되어 있다. 필요할 경우, 4개의 주사기는 담체 대조군을 함유한다(시험 화합물이 담체를 필요로 할 경우). 나머지 주사기들은 4개의 주사기의 군에 의해 시험 물질을 함유한다.Feed materials (typically TMR (44% concentrate, 6% hay, 37% maze silage and 13% grass silage) are sieved to 1 mm and weighed accurately with 64 syringes. Four of these syringes were substrate controls, indicating gas production with no effect of the compound tested. Four different syringes were positive control, to which 0.1 mM bromoethanesulfonate was added. If necessary, the four injectors contain a carrier control (if the test compound requires a carrier). The remaining syringes contain the test substance by a group of four syringes.
배지 용액의 제조: Preparation of medium solution :
성분들을 울프(Woulff) 병에서 하기 순서로 혼합한다:Ingredients are mixed in Woulff bottles in the following order:
- 711㎖ 물- 711 ml water
- 0.18㎖ 미량 원소 용액- 0.18 ml trace element solution
- 355.5㎖ 완충 용액- 355.5 ml buffer solution
- 355.5㎖ 주요 원소 용액- 355.5 ml of elemental solution
완성된 용액을 39℃로 가온한 후, 1.83㎖의 나트륨 염 용액을 첨가하고, 36℃에서 환원 용액을 첨가한다. 지시약이 무색으로 바뀔 때, 반추위액을 첨가한다.After the completed solution is warmed to 39 占 폚, 1.83 ml of a sodium salt solution is added and a reducing solution is added at 36 占 폚. When the indicator turns colorless, add ruminal juice.
반추위액의 추출: Extraction of ruminant juice :
750㎖의 반추위액을 약 1,400㎖의 배지 용액에 연속된 교반 및 CO2-가스발생하에 첨가한다.750 ml of rumen juice is added to approximately 1,400 ml of the medium solution under continuous stirring and CO 2 -gas development.
주사기 충전, 항온처리 및 기체 부피와 VFA 값의 결정: Syringe filling, heat treatment and determination of gas volume and VFA value :
희석된 반추위 유체(24㎖)를 유리 주사기에 첨가한다. 이어서 주사기를 8시간 동안 39℃에서 온화한 교반하에 배양한다. 8시간 후, 생산된 기체 부피를 측정하고, 기체 상 중 메탄의 백분율을 기체 크로마토그래피로 결정한다.Dilute rumen fluid (24 mL) is added to the glass syringe. The syringe is then incubated for 8 hours at 39 ° C with gentle agitation. After 8 hours, the volume of gas produced is measured and the percentage of methane in the gas phase is determined by gas chromatography.
결과result
발효된 식품은 인공 TMR(44% 농축물, 6% 건초, 37% 메이즈 사일리지 및 13% 목초 사일리지)이었다. 실시예 2 내지 14에 기재된 바와 같이 생산된 화합물을 건조 물질(DM) 2 내지 0.005%의 농도로 발효 주사기에 첨가하였다. 결과를 하기 표에 제시한다.Fermented foods were artificial TMR (44% concentrate, 6% hay, 37% maze silage and 13% grass silage). The compounds produced as described in Examples 2-14 were added to the fermenting syringe at a concentration of 2 to 0.005% dry matter (DM). The results are shown in the following table.
실시예 2: 비교 실시예: 메탄 생산을 위한 시험관내 시험 Example 2 : Comparative Example: In-vitro testing for methane production
실시예 1에 기재된 바와 동일한 시험관내 분석을, 니트로옥시기가 다른 유기 기로 치환된 일련의 분자로 행하였다. 또한, NaNO3 무기 염을 시험하였다. 표 4에 결과를 나타내었다. 이 데이터는 일련의 분자에 니트로옥시기가 존재하는 경우에만 상당한 메탄 감소 활동이 관찰됨을 증명한다.The same in vitro analysis as described in Example 1 was performed on a series of molecules in which the nitrooxy group was replaced with another organic group. In addition, NaNO 3 inorganic salts were tested. Table 4 shows the results. This data demonstrates that significant methanogenic activity is observed only when nitrooxy groups are present in a series of molecules.
실시예 3: 3-니트로옥시프로판올의 합성 Example 3 : Synthesis of 3-nitrooxypropanol
100㎖ 아세토니트릴에 용해된 50.1mmol 3-브로모프로판올 및 125.25mmol 질산은을 광-차단된 플라스크에 첨가하였다. 이러한 현탁액을 21시간 동안 70℃에서 교반하였다. 실온으로 냉각한 후, 현탁액을 여과하고 진공하에 농축하였다. 잔여물을 물에 용해시키고 TMBE로 2번 추출하였다. 유기 상을 물 및 염수로 세척하고, 합하여, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하여, 5.63g을 수득하였다.50.1 mmol of 3-bromopropanol and 125.25 mmol of silver nitrate in 100 ml acetonitrile were added to the light-blocked flask. This suspension was stirred at 70 < 0 > C for 21 hours. After cooling to room temperature, the suspension was filtered and concentrated in vacuo. The residue was dissolved in water and extracted twice with TMBE. The combined organic phase was washed with water and brine, dried over Na 2 SO 4, remove the solvent in vacuo to give the 5.63g.
조질의 생성물을 실리카겔 상에서 헵테인/에틸 아세테이트 2:1를 사용하여 플래쉬 크로마토그래피로 정제하였다; 수율: 4.82g(38.8mmol, 77.4%).The crude product was purified by flash chromatography on silica gel using heptane / ethyl acetate 2: 1; Yield: 4.82 g (38.8 mmol, 77.4%).
실시예 4: 2-(하이드록시메틸)-2-(니트로옥시메틸)-1,3-프로판다이올의 합성 Example 4 : Synthesis of 2- (hydroxymethyl) -2- (nitrooxymethyl) -1,3-propanediol
20㎖ 아세토니트릴에 용해된 5mmol 2-(브로모메틸)-2-(하이드록시메틸)-1,3-프로판다이올 및 15mmol 질산은을 광-차단된 플라스크에 첨가하였다. 이러한 현탁액을 24시간 동안 70℃에서 교반하였다. 실온으로 냉각한 후, 현탁액을 여과하고, 용매를 진공하에 제거하여, 3.05g을 수득하였다.5 mmol of 2- (bromomethyl) -2- (hydroxymethyl) -1,3-propanediol and 15 mmol of silver nitrate in 20 ml acetonitrile were added to the light-blocked flask. This suspension was stirred at 70 < 0 > C for 24 hours. After cooling to room temperature, the suspension was filtered and the solvent removed in vacuo to give 3.05 g.
조질의 생성물을 실리카겔 상에서 다이클로로메테인/메탄올 50:1를 사용하여 플래쉬 크로마토그래피로 정제하였다; 수율: 0.36g(1.99mmol, 40.2%).The crude product was purified by flash chromatography on silica gel using dichloromethane / methanol 50: 1; Yield: 0.36 g (1.99 mmol, 40.2%).
실시예 5: 라세미체-4-페닐부테인-1,2-다이일 다이니트레이트의 합성 Example 5 : Synthesis of racemic-4-phenylbutane-l, 2-dylidonitrate
40㎖ 아세토니트릴에 용해된 7.5mmol, 4-페닐-1-뷰텐, 20.3mmol 질산은 및 7.5mmol 요오드를 광-차단된 플라스크에 첨가하였다. 이러한 현탁액을 30분 동안 25℃에서 교반하고 16시간 동안 79℃에서 교반하였다. 실온으로 냉각한 후, 현탁액을 여과하고 에틸 아세테이트로 세척하였다. 여과물을 물로 세번 추출하고, 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하여, 1.92g을 수득하였다.7.5 mmol of 4-phenyl-1-butene, 20.3 mmol of silver nitrate and 7.5 mmol of iodine dissolved in 40 ml of acetonitrile was added to the light-blocked flask. This suspension was stirred for 30 min at 25 < 0 > C and for 16 h at 79 < 0 > C. After cooling to room temperature, the suspension was filtered and washed with ethyl acetate. Filtered, extracted three times with water, washed with brine, dried over Na 2 SO 4, remove the solvent in vacuo to give the 1.92g.
조질의 생성물을 실리카겔 상에서 헥세인/에틸 아세테이트 10:1를 사용하여 플래쉬 크로마토그래피로 정제하였다; 수율: 0.52g(2.03mmol, 27%).The crude product was purified by flash chromatography on silica gel using hexane / ethyl acetate 10: 1; Yield: 0.52 g (2.03 mmol, 27%).
실시예 6: N-에틸-3-니트로옥시-프로피오닉 설포닐 아마이드의 합성 Example 6 : Synthesis of N-ethyl-3-nitrooxy-propionic sulfonylamide
플라스크에서, 5㎖ 테트라하이드로퓨란에 17mmol 3-클로로프로피오닉 설포닐 클로라이드를 용해하였다. 33.3mmol 에틸아민을 45에 걸쳐 첨가하였다. 그 후에, 용매를 진공하에서 제거하였다. 잔여물을 물에 용해시키고, 에틸 아세테이트로 세번 추출하였다. 합친 유기 상을 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하였다.In a flask, 17 mmol of 3-chloropropionic sulfonyl chloride was dissolved in 5 ml of tetrahydrofuran. 33.3 mmol ethylamine was added over 45. The solvent was then removed under vacuum. The residue was dissolved in water and extracted three times with ethyl acetate. The combined organic phases washed with brine, dried over Na 2 SO 4, the solvent was removed in vacuo.
50㎖ 아세토니트릴에 용해된 잔여물 및 60mmol 질산은을 광-차단된 플라스크에 첨가하였다. 이러한 현탁액을 41시간 동안 70℃에서 교반하였다. 실온으로 냉각한 후, 현탁액을 여과하고 진공하에 농축하였다. 잔여물을 다이클로로메텐인에 용해시키고, 물로 추출하였다. 수 상을 다시 다이클로로메테인으로 2번 세척하였다. 합친 유기 상을 물 및 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하였다: 수율: 3.05g(14.5mmol, 84.5%).The residue dissolved in 50 ml acetonitrile and 60 mmol silver nitrate were added to the light-blocked flask. This suspension was stirred at 70 < 0 > C for 41 hours. After cooling to room temperature, the suspension was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and extracted with water. The phases were washed twice more with dichloromethane. Wash the combined organic phase with water and brine, dried over Na 2 SO 4, the solvent was removed in vacuo: yield: 3.05g (14.5mmol, 84.5%) .
실시예 7: 3-니트로옥시-프로필 프로피오네이트의 합성 Example 7 : Synthesis of 3-nitrooxy-propyl propionate
10㎖ TMBE에 9.1mmol 프로피오닐 클로라이드를 용해시키고 3℃로 냉각하였다. 5ml TMBE 중의 8.25mmol 3-니트로옥시프로판올 및 9.1mmol 트라이에틸아민을 3 내지 6℃에서 5분에 걸쳐 적하하였다. 냉각 없이 2시간 30분간 교반한 후, 반응 혼합물을 1N HCl로 추출하고, 물로 2번 추출하고, 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하여, 1.35g을 수득하였다.9.1 mmol propionyl chloride was dissolved in 10 ml TMBE and cooled to 3 [deg.] C. 8.25 mmol of 3-nitrooxypropanol and 9.1 mmol of triethylamine in 5 ml TMBE were added dropwise at 3 - 6 [deg.] C over 5 minutes. After stirring for 2 h 30 min without cooling, the reaction mixture was extracted with 1N HCl, extracted twice with water, washed with brine, dried over Na 2 SO 4 and the solvent removed in vacuo to give 1.35 g .
조질의 생성물을 실리카겔 상에서 헥세인/에틸 아세테이트 4:1를 사용하여 플래쉬 크로마토그래피로 정제하였다; 수율: 1.14g(6.4mmol, 78.0%).The crude product was purified by flash chromatography on silica gel using hexane / ethyl acetate 4: 1; Yield: 1.14 g (6.4 mmol, 78.0%).
실시예 8: 3-니트로옥시-프로필 벤조에이트의 합성 Example 8 : Synthesis of 3-nitrooxy-propyl benzoate
10㎖ TMBE에 용해된 16.5mmol 3-니트로옥시프로판올 및 18.2mmol 트라이에틸아민을 3℃로 냉각하였다. 5ml TMBE 중의 18.2mmol 벤조일클로라이드를 3 내지 6℃에서 7분에 걸쳐 적하하였다. 24시간 30분간 냉각 없이 교반한 후, 반응 혼합물을 포화 NaHCO3, 물, 1N HCl로 추출하고, 물로 2번 추출하고, 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하여, 3.3g을 수득하였다.16.5 mmol 3-nitrooxypropanol and 18.2 mmol triethylamine dissolved in 10 ml TMBE were cooled to 3 < 0 > C. 18.2 mmol benzoyl chloride in 5 ml TMBE was added dropwise at 3 - 6 [deg.] C over 7 min. After stirring for 24 h 30 min without cooling, the reaction mixture is extracted with saturated NaHCO 3 , water, 1N HCl, extracted twice with water, brine, dried over Na 2 SO 4 and the solvent removed under vacuum , 3.3 g.
조질의 생성물을 실리카겔 상에서 헥세인/에틸 아세테이트 1:0 내지 2:1의 구배를 사용하여 플래쉬 크로마토그래피로 정제하였다; 수율: 0.66g(2.9mmol, 17.7%).The crude product was purified by flash chromatography on silica gel using a gradient of hexane / ethyl acetate 1: 0 to 2: 1; Yield: 0.66 g (2.9 mmol, 17.7%).
실시예 9: 3-니트로옥시-프로필 헥사노에이트의 합성 Example 9 : Synthesis of 3-nitrooxy-propyl hexanoate
10㎖ 다이에틸에터에 용해된 20mmol 3-니트로옥시프로판올 및 20mmol 트라이에틸아민을 0℃로 냉각하였다. 18.2mmol 헥소일클로라이드를 0 내지 5℃에서 5분에 걸쳐 적하하였다. 19시간 냉각 없이 교반한 후, 반응 혼합물을 1N HCl로 추출하고, 물로 2번 추출하고, 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하여, 3.1g을 수득하였다.20 mmol of 3-nitrooxypropanol and 20 mmol of triethylamine dissolved in 10 ml of diethyl ether were cooled to 0 < 0 > C. 18.2 mmol of hexyl chloride was added dropwise at 0 SIMILAR 5 DEG C over 5 minutes. 19 hours of stirring without cooling, the reaction mixture was extracted with 1N HCl, and extracted twice with water, washed with brine, dried over Na 2 SO 4, remove the solvent in vacuo to give the 3.1g.
조질의 생성물을 실리카겔 상에서 헵테인/에틸 아세테이트 4:1을 사용하여 플래쉬 크로마토그래피로 정제하였다; 수율: 2.4g(10.9mmol, 60.0%).The crude product was purified by flash chromatography on silica gel using heptane / ethyl acetate 4: 1; Yield: 2.4 g (10.9 mmol, 60.0%).
실시예 10: 3-니트로옥시-프로필 5-니트로옥시-헥사노에이트의 합성 Example 10 : Synthesis of 3-nitrooxy-propyl 5-nitrooxy-hexanoate
10㎖ 다이에틸에터에 용해된 20mmol 3-니트로옥시프로판올 및 20mmol 트라이에틸아민을 0℃로 냉각하였다. 18.2mmol 5-니트로옥시펜토일클로라이드를 0 내지 5℃에서 5분에 걸쳐 적하하였다. 냉각 없이 밤새 교반한 후, 반응 혼합물을 1N HCl로 추출하고, 물로 2번 추출하고, 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하였다.20 mmol of 3-nitrooxypropanol and 20 mmol of triethylamine dissolved in 10 ml of diethyl ether were cooled to 0 < 0 > C. 18.2 mmol of 5-nitrooxypentyl chloride was added dropwise at 0 SIMILAR 5 DEG C over 5 minutes. After stirring overnight without cooling, the reaction mixture was extracted with 1N HCl, extracted twice with water, washed with brine, dried over Na 2 SO 4, the solvent was removed in vacuo.
조질의 생성물을 실리카겔 상에서 헵테인/에틸 아세테이트 4:1을 사용하여 플래쉬 크로마토그래피로 정제하였다; 수율: 2.4g(9.1mmol, 50.0%).The crude product was purified by flash chromatography on silica gel using heptane / ethyl acetate 4: 1; Yield: 2.4 g (9.1 mmol, 50.0%).
실시예 11: 벤질니트레이트의 합성 Example 11 : Synthesis of benzyl nitrate
80㎖ 아세토니트릴에 용해된 10mmol 벤질브로마이드 및 12mmol 질산은을 광-차단된 플라스크에 첨가하였다. 이러한 현탁액을 5시간 동안 70℃에서 교반하였다. 실온으로 냉각한 후, 현탁액을 여과하고 진공하에 농축하였다. 잔여물을 다이클로로메테인에 용해시키고 물로 추출하였다. 수 상을 다시 다이클로로메테인으로 2번 세척하였다. 합친 유기 상을 물 및 염수로 세척하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하였다: 수율: 1.55g(10.1mmol, 100%).10 mmol of benzyl bromide and 12 mmol of silver nitrate dissolved in 80 ml of acetonitrile were added to the light-blocked flask. This suspension was stirred at 70 < 0 > C for 5 hours. After cooling to room temperature, the suspension was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and extracted with water. The phases were washed twice more with dichloromethane. Wash the combined organic phases with water and brine, dried over Na 2 SO 4, the solvent was removed in vacuo: yield: 1.55g (10.1mmol, 100%) .
실시예 12: 1,3-비스-니트로옥시-프로페인의 합성 Example 12 : Synthesis of 1,3-bis-nitrooxy-propane
20.0㎖의 무수 아세토니트릴 중 1,3-다이브로모프로페인(2.00g, 1.0당량)의 용액에 질산은(3.70g, 2.2당량)을 첨가하였다. 반응 혼합물을 암실에서 70℃에서 2시간 동안 가열하였다. 생성된 혼합물을 셀라이트를 통해 여과하고 여과물을 농축하였다. 잔여물을 물(50.0 ㎖)에 용해시키고, 다이클로로메테인(2 x 50.0㎖)으로 추출하고, 황산 마그네슘 상에서 건조시키고, 용매를 진공하에 증발시켜, 화합물 1.44g을 무색 액체로서 수득하였다(수율 = 87%).Silver nitrate (3.70 g, 2.2 eq) was added to a solution of 1,3-dibromopropane (2.00 g, 1.0 eq) in 20.0 mL of anhydrous acetonitrile. The reaction mixture was heated in a dark room at 70 < 0 > C for 2 hours. The resulting mixture was filtered through celite and the filtrate was concentrated. The residue was dissolved in water (50.0 mL), extracted with dichloromethane (2 x 50.0 mL), dried over magnesium sulfate and the solvent was evaporated in vacuo to give 1.44 g of the compound as a colorless liquid = 87%).
실시예 13: 1,4-비스-니트로옥시-뷰테인의 합성 Example 13 : Synthesis of 1,4-bis-nitrooxy-butane
20.0㎖의 무수 아세토니트릴 중 1,4-다이브로모뷰테인(2.00g, 1.0당량)의 용액에 질산은(3.50g, 2.2당량)을 첨가하였다. 반응 혼합물을 암실에서 70℃에서 2시간 동안 가열하였다. 생성된 혼합물을 셀라이트를 통해 여과하고 여과물을 농축하였다. 잔여물을 물(50.0 ㎖)에 용해시키고, 다이클로로메테인(2 x 50.0㎖)으로 추출하고, 황산 마그네슘 상에서 건조시키고, 용매를 진공하에 증발시켜, 화합물 1.49g을 무색 액체로서 수득하였다(수율 = 89%).Silver nitrate (3.50 g, 2.2 eq) was added to a solution of 1,4-dibromobutaine (2.00 g, 1.0 eq) in 20.0 mL anhydrous acetonitrile. The reaction mixture was heated in a dark room at 70 < 0 > C for 2 hours. The resulting mixture was filtered through celite and the filtrate was concentrated. The residue was dissolved in water (50.0 mL), extracted with dichloromethane (2 x 50.0 mL), dried over magnesium sulfate and the solvent evaporated in vacuo to afford 1.49 g of the compound as a colorless liquid = 89%).
실시예 14: 1,5-비스-니트로옥시-펜테인의 합성 Example 14 : Synthesis of 1,5-bis-nitrooxy-pentane
20.0㎖의 무수 아세토니트릴 중 1,5-다이브로모펜테인(2.00g, 1.0당량)의 용액에 질산은(3.30g, 2.2당량)을 첨가하였다. 반응 혼합물을 암실에서 70℃에서 2시간 동안 가열하였다. 생성된 혼합물을 셀라이트를 통해 여과하고 여과물을 농축하였다. 잔여물을 물(50.0 ㎖)에 용해시키고, 다이클로로메테인(2 x 50.0㎖)으로 추출하고, 황산 마그네슘 상에서 건조시키고, 용매를 진공하에 증발시켜, 화합물 1.38g을 무색 액체로서 수득하였다(수율 = 82%).Silver nitrate (3.30 g, 2.2 eq.) Was added to a solution of 1,5-dibromopentane (2.00 g, 1.0 eq) in 20.0 mL anhydrous acetonitrile. The reaction mixture was heated in a dark room at 70 < 0 > C for 2 hours. The resulting mixture was filtered through celite and the filtrate was concentrated. The residue was dissolved in water (50.0 mL), extracted with dichloromethane (2 x 50.0 mL), dried over magnesium sulfate and the solvent was evaporated in vacuo to give 1.38 g of the compound as a colorless liquid = 82%).
실시예 15: 5-니트로옥시-펜테인니트릴의 합성 Example 15 : Synthesis of 5-nitrooxy-pentenenitrile
40.0㎖의 무수 아세토니트릴 중 5-브로모발레로니트릴(4.00g, 1.0당량)의 용액에 질산은(4.60g, 1.1당량)을 첨가하였다. 반응 혼합물을 암실에서 70℃에서 2시간 동안 가열하였다. 생성된 혼합물을 셀라이트를 통해 여과하고 여과물을 농축하였다. 잔여물을 물(50.0 ㎖)에 용해시키고, 다이클로로메테인(2 x 50.0㎖)으로 추출하고, 황산 마그네슘 상에서 건조시키고, 용매를 진공하에 증발시켜, 화합물 3.56g을 무색 액체로서 수득하였다(수율 = 99%).To a solution of 5-bromo valeronitrile (4.00 g, 1.0 eq) in 40.0 mL of anhydrous acetonitrile was added silver nitrate (4.60 g, 1.1 eq). The reaction mixture was heated in a dark room at 70 < 0 > C for 2 hours. The resulting mixture was filtered through celite and the filtrate was concentrated. The residue was dissolved in water (50.0 mL), extracted with dichloromethane (2 x 50.0 mL), dried over magnesium sulfate and the solvent was evaporated in vacuo to give 3.56 g of the compound as a colorless liquid = 99%).
실시예 16: 비스-(2-니트로옥시에틸) 에터의 합성 Example 16 : Synthesis of bis- (2-nitrooxyethyl) ether
30㎖ 아세토니트릴에 용해된 16.05mmol 비스-(2-브로모에틸) 에터 및 40.13mmol 질산은을 광-차단된 플라스크에 첨가하였다. 이러한 현탁액을 16시간 동안 70℃에서 교반하였다. 실온으로 냉각한 후, 현탁액을 여과하고 진공하에 농축하였다. 잔여물을 물에 용해시키고 TMBE로 2번 추출하였다. 유기 상을 물 및 염수로 세척하고, 합하고, Na2SO4 상에서 건조시키고, 용매를 진공하에 제거하여, 3.06g을 수득하였다. 조질의 생성물을 실리카겔 상에서 헵테인/에틸 아세테이트 1:1을 사용하여 여과하였다; 수율: 2.94g(15.0mmol, 93.4%).16.05 mmol bis- (2-bromoethyl) ether and 40.13 mmol silver nitrate dissolved in 30 ml acetonitrile were added to the light-blocked flask. This suspension was stirred at 70 < 0 > C for 16 hours. After cooling to room temperature, the suspension was filtered and concentrated in vacuo. The residue was dissolved in water and extracted twice with TMBE. Were combined and the organic phase was washed with water and brine, dried over Na 2 SO 4, remove the solvent in vacuo to give the 3.06g. The crude product was filtered on silica gel using heptane / ethyl acetate 1: 1; Yield: 2.94 g (15.0 mmol, 93.4%).
실시예 17: 에틸-3-니트로옥시프로피오네이트에 비교한 3-니트로옥시프로판올의 생체내 효과 Example 17 : In vivo effect of 3-nitrooxypropanol compared to ethyl-3-nitrooxypropionate
재료 및 방법Materials and methods
10마리의 양의 반추위에 케뉼라를 삽입하였다. 시험은 수술한 지 한 달 후에 시작하였다. 3개의 처리군이 있었다(대조군, 첨가제 1 및 첨가제 2, 둘 다 단일 복량). 첨가제 1은 에틸-3-니트로옥시프로피오네이트이고, 첨가제 2는 본 발명의 3-니트로옥시프로판올이다. 실험 고안은 각각의 기간 내 처리군당 3마리의 양 및 3회 연속기간에 의한 3 × 3 라틴(Latin) 스퀘어로 구성되었다. 각각의 기간은, 처리에 대한 28일의 적응기간 + 챔버에서 연속적인 2일의 메탄 측정 및 반추위 샘플의 수집기간을 포함한다. 적응 단계의 과정상에서, 14일째에는 중간 기간 1일의 메탄 측정을 수행하였다. 또한, 22일 및 23일째 동안에는, 나일론 백에 보관한 알팔파 건초 및 귀리의 샘플을 양의 반추위에서 배양하여 건조 물질의 반추위 분해를 결정하였다. 챔버에서의 메탄 측정의 2일 동안(29일 및 30일)에는, 반추위 내용물 샘플을 아침 사료공급 한지 2시간 후에 수집하고, 일부를 샘플링(sub-sampling)하고, 즉시 냉동시킨 후 DNA 추출 및 휘발성 지방산과 암모니아 질소 농도 결정전까지 보관하였다. 실험 동물을 3마리의 동물로 이루어진 3개의 하위 군으로 무작위적으로 할당하고 3개의 처리군중 하나씩 무작위적으로 분배하였다(대조군, 첨가제 1 및 첨가제 2). 3개의 하위 군은, 챔버에서 메탄을 측정하기 전에, 동일한 적응일에 있도록 2일의 기간동안의 식이에 대한 적응으로 시작하였다. 동물을 각각 신선한 물에 항상 접근할 수 있는 우리에 가두었다. 15 내지 20㎝로 절단된 알팔파 건초 및 귀리 60:40 비율에 무기물-비타민 보충물이 더해진 식이를, 약 1.1배 에너지 유지 수준으로 2회의 동일한 식사로 9시 및 14시에 동물에게 제공하였다. 신선한 물질 섭취량을 시험기간 전반에 걸쳐 각각의 동물에 대해 매일 관찰하였다.A cannula was inserted into the rumen of 10 sheep. The test started one month after surgery. There were three treatment groups (control, additive 1 and additive 2, both single doses). Additive 1 is ethyl-3-nitrooxypropionate, and Additive 2 is 3-nitrooxypropanol of the present invention. The experimental design consisted of 3 x 3 Latin squares per treatment group and three consecutive periods in each period. Each period includes an adaptation period of 28 days for the treatment + two consecutive days of methane measurement in the chamber and a collection period of the rumen sample. During the course of the adaptation phase, a methane measurement of the first day of the intermediate period was performed on the 14th day. Also, during days 22 and 23, samples of alfalfa hay and oats stored in nylon bags were cultured in positive rumen to determine rumen degradation of the dry material. During two days (29 and 30 days) of methane measurement in the chamber, the rumen content samples were collected 2 hours after feeding the morning, some were sub-sampled, immediately frozen and then subjected to DNA extraction and volatilization Fatty acid and ammonia nitrogen were stored until the concentration was determined. The experimental animals were randomly assigned to three subgroups of three animals and randomly distributed in one of three treatment groups (control, additive 1 and additive 2). The three subgroups began with an adaptation to the diet for a period of two days, so that the same adaptation day was allowed before measuring methane in the chamber. Each animal was confined to us, who always had access to fresh water. Alfalfa hay cut to 15-20 cm and an oat 60:40 ratio supplemented with mineral-vitamin supplements were given to the animals at 9 and 14 o'clock with two identical meals at an energy maintenance level of about 1.1 times. Fresh material intake was monitored daily for each animal throughout the test period.
첨가제를 사료와 동시에 반추위 캐뉼라(cannula)를 통해 1일 2회 제공하였다. 각각의 첨가제에 상응하는 양(첨가제 둘 다에 대해 동물당 하루에 100mg)을 10그램의 분쇄 귀리에 첨가하고, 셀룰로스 페이퍼에 싼 직후 이를 반추위에 넣었다. 활성 분자가 휘발성이기 때문에, 상기 언급된 과정은 4℃의 냉장실에서 수행되었다.The additives were provided twice a day via a rumen cannula at the same time as the feed. The amount corresponding to each additive (100 mg per animal per day for both additives) was added to 10 grams of ground oats, which were placed in rumen immediately after being wrapped in cellulose paper. Since the active molecule is volatile, the above-mentioned procedure was performed in a cold room at 4 占 폚.
메탄 측정 및 샘플 수집Methane measurement and sample collection
4개의 메탄 챔버 세트를 사용하였다. 14일, 29일 및 30일째에 동물을 메탄 측정용 챔버에 위치시켰다. 각각의 챔버는 1.8m 폭 × 1.8m 깊이 × 1.5m 높이였다. 챔버 공기 온도는 15 내지 20℃로 유지되었다. 각각의 챔버 내에서, 동물을 적응 기간에서와 동일한 우리에 개별적으로 감금시켰다. 매일 9시에 챔버 바닥을 청소하고 동물에게 사료공급할 때 중단이 있었다. 플럭스를 1일 3회 계산한 후 평균하여 23시간 방출값을 얻었기 때문에, 이러한 중단은 1일 메탄 방출량에는 거의 영향을 주지 않았다. 각각의 챔버의 유입 도관 및 유출 도관에 대해 공기 흐름 및 메탄의 농도를 측정하였다. 공기 속도는 각각의 챔버에 대한 배기 도관에서 그 날에 걸쳐 연속적으로 관찰하였다. 각각의 4개의 도관(챔버 1, 2 및 3, 및 기준)에서 공기 스트림을 샘플링하고, 기체 분석기 ADM MGA3000(영국 허츠 소재의 스펄링 웍스(Spurling works))을 사용하여 메탄 농도를 연속적으로 측정하였다. 챔버에서 모든 유입 및 배기 도관 중의 공기 흐름을 연속하여 샘플링하는데에 11분이 소요되었다(챔버 1, 2 및 3에서 3분, 기준의 경우 2분). 요약하면, 신선한 공기 유입 및 챔버 배기 메탄 농도의 차이 및 평균 공기 속도로부터 각각의 측정일 동안 각각의 챔버에 대한 메탄의 플럭스를 계산하였다.Four methane chamber sets were used. On days 14, 29 and 30, the animals were placed in a chamber for methane measurement. Each chamber was 1.8 m wide x 1.8 m deep x 1.5 m high. The chamber air temperature was maintained at 15-20 < 0 > C. Within each chamber, the animals were individually housed in the same cage as in the adaptation period. There was a break at 9 o'clock every day to clean the chamber floor and feed the animals. Since the flux was calculated three times a day and then averaged to obtain a discharge value of 23 hours, this discontinuation had little effect on daily methane emissions. Air flow and methane concentrations were measured for the inlet and outlet conduits of each chamber. Air velocities were continuously monitored over the day in the exhaust conduit for each chamber. The air stream was sampled at each of the four conduits (chambers 1, 2 and 3, and reference) and the methane concentration was continuously measured using a gas analyzer ADM MGA3000 (Spurling works, Hertz, UK) . It took 11 minutes to continuously sample the air flow in all the inlet and exhaust ducts in the chamber (3 minutes in chambers 1, 2 and 3, 2 minutes in the standard case). In summary, methane flux for each chamber was calculated for each measurement day from the difference in fresh air inlet and chamber exhaust methane concentrations and the average air velocity.
반추위 샘플 분석Rumen sample analysis
반추위 내용물의 샘플을 동결 건조시키고, 비이드 비터(bead beater)(미니-비이드 비터(Mini-bead Beater); 미국 오클라호마주 바틀레스빌 소재의 바이오스펙 프로덕츠(BioSpec Products))를 사용하여 물리적 교란에 의해 철저히 혼합한 후 DNA를 추출하였고, 이는 약 50㎎의 샘플로부터 퀴아암프(QIAamp: 등록상표) DNA 스툴 미니 키트(Stool Mini Kit, 영국 웨스트 서섹스 소재의 퀴아겐 리미티드(Qiagen Ltd))를 사용하여 제조업체의 지시에 따라 용해 배양에 더 높은 고온(95℃)을 사용하도록 변형하여 수행하였다. DNA 샘플을 정량적 실시간 PCR(qPCR) 증폭을 위한 주형으로 사용하였다. 총 박테리아, 총 원생동물 및 총 메탄생성 고세균(archaea)의 수를 실시간-PCR(qPCR)로 정량화하였다. 상이한 프라이머 세트를 사용하여 16S rRNA 유전자-타겟화된 총 박테리아(Maeda et al., 2003), 및 18S rRNA 유전자-타겟화된 총 원생동물(Sylvester et al., 2005)을 증폭시켰다. 메탄생성 고세균의 검출을 위해 고안된 프라이머를 메틸 조효소-M 환원효소(mcrA) 유전자에 대해 타겟화하였다(Denman et al.,2007). 증폭 혼합물은 23㎕의 최종 부피에 11.5㎕의 2X RT-PCR 수퍼믹스(supermix) 바이오-래드(Bio-Rad, 미국 캘리포니아주 헤르큘레스 소재의 바이오-래드 래보레이토리즈 인코퍼레이트(Bio-Rad Laboratories Inc.)), 0.4㎕의 각각의 프라이머 및 0.5㎕의 샘플을 함유하였다. 각각의 쌍의 프라이머에 대해 증폭 효능을 하기 프로그램으로 평가하였다: 95℃에서 5분 주기, 95℃에서 15초, 60℃에서 30초, 72℃에서 55초, 및 형광 발광 측정을 위한 75℃에서 6초의 주기 40회. 55℃에서 95℃로 온도를 증가시킴으로써 용융 곡선을 작성하고, 매 5℃ 마다 판독하였다. 각각의 타깃 군의 증폭을 하기 프로그램으로 수행하였다: 95℃에서 5분 주기, 95℃에서 15초, 60℃에서 15초 및 72℃에서 45초의 주기 40회(형광 발광 측정 포함), 및 45℃의 설정값 온도 내지 95℃의 종료 온도의 용융 곡선. DNA 복제물의 수로서 표시되는, 박테리아, 원생동물 및 메탄생성 고세균의 절대량을, 표준물로서 플라스미드 pCR(등록상표)4-TOPO(인비트로겐(Invitrogen: 등록상표), 미국 캘리포니아주 칼스바드)를 사용하여 결정하였다. 각각의 프라이머 세트를 사용하여 수득된 PCR 생성물을 정제하고, 이어서 pCR(등록상표) 4-TOPO(등록상표) 플라스미드(미국 캘리포니아주 칼스바드 소재의 인비트로겐(등록상표))로 클로닝하여 재조합 플라스미드를 생산하였다. PCR을 사용하여 예상된 삽입물에 대해 확인된 단일 콜로니를, 항생제 및 X-gal을 갖는 고체 배지에서 하룻밤 성장시켰다. 이후, 형질전환된 이. 콜라이(E. coli) 콜로니의 스크리닝을 수행하고 양성 콜로니들중 일부를 무작위적으로 선택하였다. PCR에 의해 콜로니중 삽입된 단편의 존재를 검토한 후, 양성 콜로니의 대량 배양을 액체 배지에서 하룻밤 수행하였다. 이들 배양에 속하는 플라스미드를 퓨어 링크(Pure Link: 등록상표) 미니프렙(Miniprep) 키트(인비트로겐(등록상표), 미국 캘리포니아주 칼스바드)를 사용하여 추출하였고, 이어서 서열화하여 삽입된 단편의 존재를 확인하였다. 플라스미드 추출물에 존재하는 16S rRNA 유전자 복제물의 수를 플라스미드 DNA 농도 및 삽입물을 갖는 벡터의 분자량을 사용하여 계산하였다. 농축된 플라스미드를 계대 희석하여(10배) 108 내지 102 범위의 복제물을 제공하여, 표준 곡선을 생성하였다.Samples of the ruminal contents were lyophilized and the physical disturbance was measured using a bead beater (Mini-bead Beater; BioSpec Products, Bartlesville, Oklahoma) , Which was extracted from approximately 50 mg of sample using a QIAamp (TM) DNA Stool Mini Kit (Qiagen Ltd, West Sussex, UK) (95 < 0 > C) for dissolution culture according to the manufacturer's instructions. DNA samples were used as templates for quantitative real-time PCR (qPCR) amplification. Total bacteria, total protozoa, and total methanogenic archaea were quantified by real-time PCR (qPCR). 16S rRNA gene-targeted total bacteria (Maeda et al., 2003), and 18S rRNA gene-targeted total protozoa (Sylvester et al., 2005) were amplified using different primer sets. Primers designed for the detection of methanogenic archaea were targeted against the methyl-coenzyme-M reductase (mcrA) gene (Denman et al., 2007). The amplification mixture was added to a final volume of 23 μl with 11.5 μl of 2X RT-PCR supermix Bio-Rad (Bio-Rad, Bio- Rad Laboratories, Herculex, Rad Laboratories Inc.)), 0.4 [mu] l of each primer and 0.5 [mu] l of sample. Amplification efficacy for each pair of primers was evaluated by the following program: 95 ° C for 5 minutes, 95 ° C for 15 seconds, 60 ° C for 30 seconds, 72 ° C for 55 seconds, and 75 ° C for fluorescence measurement 40 cycles of 6 seconds. Melting curves were made by increasing the temperature from 55 占 폚 to 95 占 폚 and read every 5 占 폚. Amplification of each target group was performed with the following program: 40 cycles (including fluorescence emission measurement) of 45 seconds at 95 ° C, 15 seconds at 95 ° C, 15 seconds at 60 ° C, and 45 seconds at 72 ° C, and 45 ° C Lt; RTI ID = 0.0 > 95 C. < / RTI > The absolute amount of bacterial, protozoan and methanogenic antibiotics, expressed as the number of DNA replicates, was determined using the plasmid pCR (R) 4-TOPO (Invitrogen, Carlsbad, Calif., USA) Respectively. The PCR product obtained using each primer set was purified and then cloned into pCR (R) 4-TOPO (R) plasmid (Invitrogen (R), Carlsbad, CA) to obtain a recombinant plasmid Respectively. Single colonies identified for anticipated inserts using PCR were grown overnight in solid media with antibiotics and X-gal. Thereafter, Screening of E. coli colonies was performed and some of the positive colonies were randomly selected. After reviewing the presence of the inserted fragment in the colony by PCR, a positive culture of positive colonies was performed overnight in the liquid medium. Plasmids belonging to these cultures were extracted using a Pure Link (TM) Miniprep kit (Invitrogen (R), Carlsbad, CA) and then sequenced to determine the presence of inserted fragments Respectively. The number of 16S rRNA gene copies present in the plasmid extract was calculated using the plasmid DNA concentration and the molecular weight of the vector carrying the insert. The concentrated plasmid was serially diluted (10-fold) to provide replicates ranging from 10 8 to 10 2 to generate a standard curve.
메탄생성 고세균 및 원생동물의 경우, 기준 유전자로서 16s RNA를 사용하여, 덴만과 맥스위니(Denman and McSweeny, 2006)가 기술한 바와 같이 상대적인 존재 정량화를 사용하였다. 휘발성 지방산을 기체 크로마토그래피로 분석하고, 암모니아 N 농도를 본 발명자의 실험실에서 발행된 규약(Martin-Garcia et al., 2004)에 따라 비색법에 의해 분석하였다.For methanogenic archaea and protozoa, 16s RNA was used as a reference gene and relative quantification was used as described by Denman and McWeeny (2006). Volatile fatty acids were analyzed by gas chromatography and the ammonia N concentration was analyzed by colorimetry according to the protocol issued by the inventor's laboratory (Martin-Garcia et al., 2004).
반추위 분해능Rumen resolution
2mm 분쇄 사료 3그램을 50㎛의 기공크기를 갖는 5cm × 10cm 나일론 백(#R510 안콤(Ankom) 동일 반응계 백, 뉴욕 마케돈)에 놓아두었다. 동물의 식이에 사용된 두 성분을 시험하였다: 귀리 및 알팔파 건초. 귀리가 있는 백을 24시간동안 반추위에서 배양하였고, 알팔파 건초는 48시간동안 배양하였다. 다른 사료의 반추위에서의 평균 체류 시간을 기준으로 배양 시간을 택하였다. 22일 및 23일째, 사료당, 동물당 및 기간당 두 개의 백을 시험하였다. 백을 반추위에 위치시키고, 즉시 아침 사료를 준다. 24시간 또는 48시간에 반추위에서 이를 꺼내고, 찬물로 세척하고, -20℃로 냉동하였다. 매 기간의 말기에, 냉동 백을, 용해도를 고려하기 위해 반추위에서 배양되지 않은 사료당 두 백을 포함하여, 단기 냉수 프로프램을 사용하여 세척 기계에서 세척하였다. 세척 후에, 백을 48시간동안 60℃의 오븐에 놓았다. 배양 시간에 걸친 건조 물질의 손실로서 반추위 분해율(%)를 산출하였다.Three grams of 2 mm ground meal was placed in a 5 cm x 10 cm nylon bag (# R510 Ankom In-Situ Bag, New York Macedon) with a pore size of 50 mu m. The two ingredients used in animal diets were tested: oats and alfalfa hay. Oat bags were cultured in rumen for 24 hours and alfalfa hay was cultured for 48 hours. The incubation time was chosen based on the average residence time in the rumen of other feeds. On days 22 and 23, two bags per feed, animal, and period were tested. Place the bag on the rumen and immediately feed the breakfast. The rumen was removed at 24 or 48 hours, washed with cold water, and frozen at -20 ° C. At the end of each period, the frozen bags were washed in a washing machine using short-chilled cold water, including two bags per feed that were not cultured in the rumen to account for solubility. After washing, the bags were placed in an oven at < RTI ID = 0.0 > 60 C < / RTI > The rumen degradation rate (%) was calculated as the loss of dry matter over the incubation time.
실험적 동물 보호Experimental animal protection
양에 대한 모든 관리 및 실험 절차는 실험 동물 보호에 대한 스페인 가이드라인(법 제1201/2005호, 2005년 10월 10일)을 준수하여 숙련자에 의해 수행되었다. 동물의 복지 조건을 고려하여 챔버에서의 온도, 습도 및 공기 차단을 주의깊게 관찰하였다. 또한 좋은 공기 품질 및 회복 속도를 보장하는 제한치 내로 유지하기 위해 CO2 농도를 연속적으로 관찰하였다. 동물들은 챔버에서 사육하는 동안 어떠한 스트레스받은 행동을 나타내지 않았다.All management and testing procedures for sheep were carried out by an expert in accordance with the Spanish Guidelines for the Protection of Laboratory Animals (Act No. 1201/2005, 10 October 2005). The temperature, humidity, and air-tightness in the chamber were carefully observed in consideration of animal welfare conditions. The CO 2 concentration was also continuously monitored to keep within acceptable limits to ensure good air quality and recovery rates. Animals did not exhibit any stressful behavior during breeding in the chamber.
통계적 분석Statistical analysis
개별적인 메탄 방출, VFA 프로파일, 아세테이트 대 프로피오네이트 비, 암모니아 N 농도, 총 박테리아, 총 원생동물 및 메탄생성 고세균의 농도의 log10 변환 및 상대적 존재비를, 첨가제를 포함하는 것의 효과에 대해 분석하였다. 각각의 분석에 대해 평균값의 표준 오차(SEM: standard error of the mean)를 컴퓨터 분석하였다. 평균은 추가로 최소 유의적 차이(LSD: least significant difference) 시험을 사용하여 비교하였다.Log 10 conversions and relative abundance ratios of concentrations of individual methane emissions, VFA profiles, acetate to propionate ratios, ammonia N concentrations, total bacteria, total protozoa and methanogenic esters were analyzed for the effect of including additives. For each analysis, the standard error of the mean (SEM) was computerized. The averages were further compared using the least significant difference (LSD) test.
결과result
동물을 메탄 챔버에서 14일 및 30일 두는 경우, 건조 물질 섭취량은 처리에 영향을 받지않았으며(P>0.05) 섭취량에서 약간의 감소만 관찰되었다.When the animals were placed in the methane chamber for 14 and 30 days, the dry matter intake was not affected by treatment (P> 0.05) and only a slight decrease in intake was observed.
섭취량에 대해 기재하였듯이, 체중(챔버 측정 전 후 기록된 체중 평균)은 처리군들간에 상이하지 않았다(표 5). 새로운 물질 섭취량 1kg당 리터(ℓ)로 표시된 메탄 방출은, 식이에 두 첨가제가 혼입된 경우 14일째에 크게 감소하였다(P=0.020). 대조군 대비 관찰된 감소율은 첨가제 1 및 2의 경우 각각 14% 및 23%였다. 메탄 방출이 2주 후에 기록된 경우, 비록 통계적인 유의미에 다다르진 않았지만, 29일 및 30일째 여전히 수치상의 감소가 있었다(29일 및 30일째 각각 P=0.061 및 0.183). 마지막 두 연속적인 날 동안에 기록된 측정이 함께 폴링(pool)되는 경우, 추가의 효과는 별도로 고려된 값과 유사한 경향(P=0.092)를 나타낸다.As noted for intake, body weights (mean body weight recorded before and after chamber measurements) did not differ between treatment groups (Table 5). Methane emissions, expressed in liters per kilogram of new substance intake, were significantly reduced at 14 days (P = 0.020) when two additives were added to the diet. The observed reduction rates for the Additives 1 and 2 were 14% and 23%, respectively. When methane emissions were recorded after 2 weeks, there was still a numerical decrease (P = 0.061 and 0.183 at 29 and 30 days, respectively) on day 29 and 30, although not statistically significant. When the measurements recorded during the last two consecutive days are pooled together, the additional effect shows a trend similar to the separately considered value (P = 0.092).
a,b공통의 상첨자를 공유하지 않은 열에서의 값은 상당히 상이하다(P<0.05) a, b Values in columns that do not share a common superscript are significantly different (P <0.05)
*챔버 측정 전 후 측정된 평균 * Average measured before and after chamber measurement
SEM: 평균의 표준 오차SEM: standard error of mean
a,b공통의 상첨자를 공유하지 않은 열에서의 값은 상당히 상이하다(P<0.05) a, b Values in columns that do not share a common superscript are significantly different (P <0.05)
SEM: 평균의 표준 오차SEM: standard error of mean
29일 및 30일째 수집한 반추위 샘플로부터 반추위 발효 매개변수를 연구한 결과, 발효 경로에서, 대조군과 비교할 때 첨가제 둘 다를 받은 동물의 반추위에서 더욱 많은 프로피오네이트 유형 프로파일로의 전이가 있음을 알 수 있었다(표 5). 결과적으로, 두 처리에서 아세테이트 대 프로피오네이트의 비는 상당히 감소되었다(P=0.002). 암모니아 N의 농도는 처리군들 간에 유사하고, 동물에게 공급된 식이에 대해 예측되는 범위내에 있었다.Studies of ruminal fermentation parameters from ruminal samples collected on days 29 and 30 show that there is a greater transition from the rumen of the animal receiving the additive to the more propionate type profile in the fermentation pathway compared to the control (Table 5). As a result, the ratio of acetate to propionate in both treatments was significantly reduced (P = 0.002). The concentration of ammonia N was similar between the treatment groups and within the range predicted for the diets fed to the animals.
22일 및 23일째의 인 사코(in sacco) 분해 연구는, 알팔파 건초 및 귀리 둘 다의 반추위 분해능에 첨가제 처리가 아무런 영향을 미치지 않음을 보여준다.The in-sacco digestion studies at days 22 and 23 show that additive treatment has no effect on the ruminal resolution of both alfalfa hay and oats.
반추위에서 분석한 미생물 군의 전체 및 상대적인 농도는 처리군들 간에 차이가 없음을 보여준다(P>0.05). 원생동물 및 메탄생성 고세균 둘 다의 존재비가 총 박테리아의 대해 표현된 경우, 동일한 영향 결여가 관찰되었다.The total and relative concentrations of the microbial groups analyzed in the rumen showed no difference between the treatment groups (P> 0.05). If the abundance ratio of both protozoa and methanogenic cocci were expressed for total bacteria, the same effect loss was observed.
결론conclusion
두 첨가제의 사용은 상당한 메탄 생산의 감소를 나타냈고, 또한 VFA 프로파일에 따르면, 첨가제에 의해 또한, H2 수송을 포함하는 대사 경로에서 전이가 촉진되었다. 이 시험의 목적은, 한달 간의 동물의 처리가 2주 처리 동안에 걸쳐 관찰된 결과의 지속성을 나타내는지 여부를 확인하는 것이었다. 이는 사료 첨가제의 실제 사용의 적합성을 평가할 때 필수적이다. 본 연구에서 두 첨가제는 한달 처리 기간에 걸친 메탄 방출에 대한 효과를 보여주었으며, 이는 발효 패턴의 변화에 의해 추가로 확인되었다.The use of both additives showed a significant reduction in methane production, and according to the VFA profile, the addition also promoted the metastasis in the metabolic pathway involving H 2 transport. The purpose of this test was to ascertain whether the treatment of the animals for one month represents the persistence of the results observed over the course of two weeks. This is essential in assessing the suitability of the feed additive for actual use. In this study, the two additives showed an effect on methane release over a one month treatment period, which was further confirmed by changes in the fermentation pattern.
다른 한편, 발효 패턴에서의 변화는, 메탄 생성의 감소뿐 아니라, 적은량의 아세테이트 및 아세테이트 대 프로피오네이트 비를 생성할 낮은 섬유 분해에 기인한다. 이 현상을 배제하기 위해, 동물의 반추위에서 귀리 및 알팔파 건초 둘 다를 갖는 나일론 백을 배양함으로써 반추위 분해능 평가를 수행하였다. 그 결과는 건조 물질 분해에 아무런 영향이 없다는 것을 보여주며, 이는 처리되지 않은 것과 비교하여 첨가제가 공급된 동물에서의 동일한 박테리아 및 원생동물 생물질 기록치에 의해 서로 지지된다.On the other hand, changes in the fermentation pattern are due not only to a reduction in methane production, but also to low fiber degradation which will produce a small amount of acetate and acetate to propionate ratios. To rule out this phenomenon, ruminal resolution assessments were performed by culturing nylon bags with both oats and alfalfa hay in animal rumen. The results show that there is no effect on dry matter degradation, which is supported by the same bacterial and protozoan biomarkers in the animal to which the additive is supplied compared to untreated.
실시예 18: 젖소에서 3-니트로옥시프로판올의 생체내 효과 Example 18 : In vivo effects of 3-nitrooxypropanol in cow
재료 및 방법Materials and methods
동물: 두 번 또는 그 이상의 출산 경력이 있고 550 내지 800kg 중량인 6마리의 반추위-누관 비유 홀스테인 X 프리에시안(Holstein X Friesian) 젖소를 연구에 사용하였다. 연구 초기에 소들은 중간 비유기였다. Animals : Six ruminal-follicular VU Holstein X Friesian cows with two or more births and weights ranging from 550 to 800 kg were used in the study. At the beginning of the study, the cows were mid-migratory.
실험 식이: 연구기간 내내 모든 소에게 단일의 완전 배합 사료(TMR) 식이를 제공하였다. 시험기간 동안 소들에게 자유식(ad libitum)으로 사료를 주었다. Experimental Diets : A single complete feed (TMR) diet was provided to all cattle throughout the study period. Feeding cows with ad libitum during the test period.
실험 고안: 중간 비유기의 초기에(우유 수율이 30리터 이상임), 상기 6마리의 소는 3 × 3 라틴 스퀘어 고안으로 3가지의 보충 처리군 중 하나에 무작위적으로 배당되었다(표 8). 처리 기간은 5주간 지속했다. Experimental design : At the beginning of the intermediate lactation (milk yield 30 liters or more), the 6 cows were randomly assigned to one of three supplemental treatment groups with a 3 × 3 Latin square design (Table 8). The treatment period lasted for 5 weeks.
식이: Diet:
1. 대조군1. Control group
2. 3-니트로옥시프로판올(500mg/1일)2. 3-Nitroxypropanol (500 mg / day)
3. 3-니트로옥시프로판올(2500mg/1일)3. 3-Nitroxypropanol (2500 mg / day)
3- 니트로옥시프로판올의 투여 또는 플라시보 ( placebo ): 3-니트로옥시프로판올의 투여량 또는 플라시보를 아침 및 저녁 먹이 주는 시간에 반추위 카눌라를 통해 동물에게 투여하였다. Or placebo administration of 3-nitro-oxy-propanol (placebo): the animals were administered via the rumen car Cronulla the dose or placebo for 3-nitro-oxy-propanol in the morning and evening feeding time.
기간 설계: 한번에 2마리의 소만 간접적인 열량계에 수용할 수 있기 때문에, 한쌍의 소를 한 주씩 바꾸어가며 실험하였다. 주말에 4마리의 동물을 간접적인 열량계로 이동시키고 가축우리에 각각 묶어 고정하여, 호흡의 변화(메탄 및 이산화탄소 생성과 산소의 소비)의 4가지의 완전한 24시간 측정치들을 얻었다(Cammell et al., 2000). Period design : As it can accommodate two small calories indirectly at a time, we experimented with changing a pair of cows one week. On weekends, four animals were transferred to an indirect calorimeter and each was tied up in livestock to obtain four complete 24-hour measurements of respiratory changes (methane and carbon dioxide production and oxygen consumption) (Cammell et al. 2000).
결과result
사료 섭취: 일일 건조 물질 섭취량(DMI)에 미치는 생성물(3-니트로옥시프로판올)의 큰 영향은 없었다(표 9 참고). Feed intake : There was no significant effect of the product (3-nitrooxypropanol) on the daily dry matter intake (DMI) (see Table 9).
메탄 생성: 메탄 생성(ℓ/1일) 및 메탄 수율(ℓ/kg DMI)는 3-니트로옥시프로판올에 의해 상당히 감소하였다. 메탄 생성은, 500mg/일 및 2500mg/일 투여량을 주었을때 각각 대조군 값의 93% 및 90%였다(표 9 참고). 메탄 수율과 관련해서는, 해당 값은 적고 많은 투여량에 대해 각각 대조군 메탄 수율의 96% 및 93%였다. Methane formation : methane production (l / day) and methane yield (l / kg DMI) were significantly reduced by 3-nitrooxypropanol. Methane production was 93% and 90% of the control value, respectively, given the 500 mg / day and 2500 mg / day doses (see Table 9). With respect to methane yield, the corresponding values were low and 96% and 93% of the control methane yield, respectively, for large doses.
몇몇 동물들은 다른 동물들보다 더 반응을 보이여, 동물들간에 큰 변화가 관찰되었다. 이 결과는 젖소에서의 메탄 생성의 감소에 대한 본 발명의 화합물의 잠재력을 보여주며, 사료 제제의 추가 개선에 여지가 생겼다.Some animals reacted more than other animals, and large changes were observed between animals. This result shows the potential of the compounds of the invention for the reduction of methane production in dairy cows, and there is room for further improvement of the feed formulation.
Claims (17)
하기 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 유기 분자 또는 이의 염을 하나 이상 포함하되,
Ⅰ
상기 식에서,
Y는 CaHbOdNeSg의 조성의 유기 분자로서, 이때 a는 1 내지 25 범위이며, b는 2 내지 51 범위이며, d는 0 내지 8 범위이며, e는 0 내지 5 범위이며, g는 0 내지 3 범위이고;
상기 화학식 I의 유기 분자가 하기 화학식 III의 화합물이되,
III
상기 식에서,
n은 0 내지 12 범위이며, 이때 n ≠ 0이면, 탄소 쇄는, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 치환될 수 있는 선형, 환형 또는 분지형 지방족 탄소 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태인 알케닐 또는 알키닐 탄소 쇄이며,
R4는 독립적으로, 수소 또는 1 내지 12개의 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형, 환형 또는 분지형 쇄이며,
X는 수소, R5, R5≡N, -OR5, -OCOR5, -NR5R6, -ONO2, -COOR5, -CONR5R6, -NHSO2R5, 또는 -SO2NHR5이며,
R5 및 R6은 독립적으로, 수소, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 치환된 C1 내지 C12의 선형, 분지형 또는 환형 알킬 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 알케닐 또는 알키닐 탄소 쇄이고;
하기 화학식 II로 정의되는 니트로옥시 알칸산 또는 이의 유도체는 제외되고,
II
상기 식에서,
u는 0 내지 23 범위이고, 이때 u ≠ 0이면, 탄소 쇄는, 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 선형, 환형, 또는 분지된 선형 또는 환형 지방족 탄소 쇄이며,
Z는 독립적으로, O, NH 또는 N-R3이고, 이때 R1 ≠ H이면, Z-R1-은 에스터 또는 2차 아마이드 유도체를 나타내며,
R1은 독립적으로, 수소 또는 1 내지 10개 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형, 환형 또는 분지형 쇄이며,
R2는 독립적으로, 수소 또는 1 내지 23개 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형 또는 분지형 쇄이며,
R3은 독립적으로, 수소 또는 1 내지 10개 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형, 환형 또는 분지형 쇄인, 동물 사료.As animal feeds to reduce the production of methane from ruminant digestive activity or to improve the performance of ruminants,
An organic molecule, or salt thereof, having at least one nitrooxy group substituted at any position, defined by the following formula (I)
Ⅰ
In this formula,
Y is an organic molecule having a composition of C a H b O d N e S g where a ranges from 1 to 25, b ranges from 2 to 51, d ranges from 0 to 8, e ranges from 0 to 5 And g ranges from 0 to 3;
Wherein the organic molecule of formula (I) is a compound of formula (III)
III
In this formula,
n ranges from 0 to 12, with n? 0, the carbon chain may be unsubstituted or substituted with up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups Or an alkenyl or alkynyl carbon chain which is mono-unsaturated or poly-unsaturated and in any isomeric form,
R4 is independently hydrogen or a saturated linear, cyclic or branched chain of an alkyl or alkenyl group containing from 1 to 12 carbon atoms,
X is hydrogen, R5, R5≡N, -OR5, -OCOR5 , -NR5R6, -ONO 2, -COOR5, -CONR5R6, -NHSO 2 R5, or -SO 2 NHR5,
R5 and R6 are independently selected from the group consisting of C 1 to C 12 linear, branched, or cyclic alkyl groups substituted with hydrogen, unsubstituted or up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups. Or a cyclic alkyl chain, or an alkenyl or alkynyl carbon chain which may be mono-unsaturated or poly-unsaturated and in any isomeric form;
A nitrooxyalkanoic acid or derivative thereof defined by the following formula (II) is excluded,
II
In this formula,
u ranges from 0 to 23, where u ≠ 0, the carbon chain is a linear, cyclic, or branched linear or cyclic aliphatic carbon chain, which may be singly or multiply unsaturated and in any isomeric form,
Z is independently O, NH or N-R3, wherein when R1 is not equal to H then Z-R1- represents an ester or secondary amide derivative,
R1 is independently hydrogen or a saturated linear, cyclic or branched chain of an alkyl or alkenyl group containing from 1 to 10 carbon atoms,
R2 is independently a saturated linear or branched chain of hydrogen or an alkyl or alkenyl group containing from 1 to 23 carbon atoms,
R3 is, independently, hydrogen or a saturated linear, cyclic or branched chain of alkyl or alkenyl groups containing from 1 to 10 carbon atoms.
a가 1 내지 10 범위이며, b가 2 내지 21 범위이며, d가 0 내지 6 범위이며, e가 0 내지 3 범위이며, g가 0 내지 1 범위인, 동물 사료.The method according to claim 1,
wherein a ranges from 1 to 10, b ranges from 2 to 21, d ranges from 0 to 6, e ranges from 0 to 3, and g ranges from 0 to 1.
하나 이상의 상기 화학식 I의 유기 분자 또는 이의 염이, 3-니트로옥시프로판올, 라세메이트-4-페닐부테인-1,2-다이일 다이니트레이트, 2-(하이드록시메틸)-2-(니트로옥시메틸)-1,3-프로판다이올, N-에틸-3-니트로옥시-프로피오닉 설포닐 아마이드, 5-니트로옥시-펜테인니트릴, 5-니트로옥시-펜테인, 3-니트로옥시-프로필 프로피온에이트, 1,3-비스-니트로옥시프로페인, 1,4-비스-니트로옥시부테인, 1,5-비스-니트로옥시펜테인, 3-니트로옥시-프로필 벤조에이트, 3-니트로옥시-프로필 헥사노에이트, 3-니트로옥시-프로필 5-니트로옥시 헥사노에이트, 벤질니트레이트, 아이소소르비드-다이니트레이트, N-[2-(니트로옥시)에틸]-3-피리딘카복사마이드, 2-니트로-5-니트로옥시메틸-퓨란, 및 비스-(2-니트로옥시에틸) 에터로부터 선택된, 동물 사료.The method according to claim 1,
Wherein at least one of the organic molecules of Formula I or salts thereof is selected from the group consisting of 3-nitrooxypropanol, racemate-4-phenylbutane-1,2-dyadinonitrate, 2- (hydroxymethyl) -2- N-ethyl-3-nitrooxy-propionyl sulfonylamide, 5-nitrooxy-pentenenitrile, 5-nitrooxy-pentane, 3-nitrooxy-propyl Propionate, 1,3-bis-nitrooxypropane, 1,4-bis-nitrooxybutane, 1,5-bis-nitrooxypentane, 3-nitrooxy- Propyl hexanoate, 3-nitrooxy-propyl 5-nitrooxyhexanoate, benzylnitrate, isosorbide-dinitrate, N- [2- (nitrooxy) ethyl] -3-pyridinecarboxamide, 2-nitro-5-nitrooxymethyl-furan, and bis- (2-nitrooxyethyl) ether.
하나 이상의 상기 화학식 I의 유기 분자 또는 이의 염이, 3-니트로옥시프로판올, 5-니트로옥시-펜테인니트릴, 5-니트로옥시-펜테인, 3-니트로옥시-프로필 프로피오네이트, 1,3-비스-니트로옥시프로페인, 1,4-비스-니트로옥시부테인, 1,5-비스-니트로옥시펜테인, 3-니트로옥시-프로필 벤조에이트, 3-니트로옥시-프로필 헥사노에이트, 3-니트로옥시-프로필 5-니트로옥시-헥사노에이트, 아이소소르비드-다이니트레이트, N-[2-(니트로옥시)에틸]-3-피리딘카복스아마이드, 및 비스-(2-니트로옥시에틸) 에터로부터 선택된, 동물 사료.The method according to claim 1,
Wherein at least one of the organic molecules of Formula I or salts thereof is selected from the group consisting of 3-nitrooxypropanol, 5-nitrooxy-pentenenitrile, 5-nitrooxy-pentene, 3- 3-nitrooxy-propyl benzoate, 3-nitrooxy-propyl hexanoate, 3-nitro-oxypropane, 3- (2-nitrooxyethyl) -3-pyridinecarboxamide, and bis- (2-nitrooxyethyl) Animal feed selected from ether.
하나 이상의 상기 화학식 I의 유기 분자가 3-니트로옥시 프로판올과 1,3-비스-니트로옥시프로페인의 혼합물인, 동물 사료.The method according to claim 1,
Wherein the at least one organic molecule of formula (I) is a mixture of 3-nitrooxypropanol and 1,3-bis-nitrooxypropane.
하나 이상의 상기 화학식 I의 유기 분자 또는 이의 염이, 다이알릴 다이설파이드, 마늘 기름(garlic oil), 알릴 아이소티오시아네이트, 데옥시콜산, 케노데옥시콜산 및 이들의 유도체로 구성된 군으로부터 선택된 하나 이상의 추가 활성 물질과 조합된, 동물 사료.The method according to any one of claims 1, 2, and 4 to 6,
At least one of the organic molecules of formula I or salts thereof is at least one selected from the group consisting of diallyl disulfide, garlic oil, allyl isothiocyanate, deoxycholic acid, chenodeoxycholic acid, and derivatives thereof Animal feed in combination with additional active substances.
상기 반추동물이 소, 염소, 양, 기린, 미국 들소, 유럽 들소, 야크(yak), 물소, 사슴, 낙타, 알파카(alpaca), 라마, 누(wildebeest), 영양, 가지뿔영양(pronghorn), 및 닐가이 영양(nilgai)으로 구성된 군으로부터 선택된, 동물 사료.The method according to any one of claims 1, 2, and 4 to 6,
Wherein the ruminant is selected from the group consisting of cattle, goats, sheep, giraffes, American bison, European bison, yak, buffalo, deer, camel, alpaca, llama, wildebeest, nutrition, pronghorn, ≪ / RTI > and nilgai (nilgai).
건조 물질 섭취량(㎏) 당 리터(ℓ)로 계산된 반추동물에서의 메탄 생산량이 대사 챔버(metabolic chamber)에서 측정시 10% 이상 감소되는, 동물 사료.The method according to any one of claims 1, 2, and 4 to 6,
Animal feeds in which the methane production in ruminants calculated in liters per liter of dry matter intake (㎏) is reduced by more than 10% when measured in the metabolic chamber.
반추동물에게 투여되는 하나 이상의 상기 화학식 I로 정의된 활성 화합물의 양이 사료(㎏) 당 1 ㎎ 내지 10 g인, 동물 사료.The method according to any one of claims 1, 2, and 4 to 6,
Wherein the amount of at least one of the active compounds defined by formula (I) administered to the ruminant is between 1 mg and 10 g per kg of feed.
상기 화학식 I의 유기 분자가 하기 화학식 III의 화합물이되,
III
상기 식에서,
n은 0 내지 12 범위이며, 이때 n ≠ 0이면, 탄소 쇄는, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 치환될 수 있는 선형, 환형 또는 분지형 지방족 탄소 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태인 알케닐 또는 알키닐 탄소 쇄이며,
R4는 독립적으로, 수소 또는 1 내지 12개의 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형, 환형 또는 분지형 쇄이며,
X는 수소, R5, R5≡N, -OR5, -OCOR5, -NR5R6, -ONO2, -COOR5, -CONR5R6, -NHSO2R5, 또는 -SO2NHR5이며,
R5 및 R6은 독립적으로, 수소, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 치환된 C1 내지 C12의 선형, 분지형 또는 환형 알킬 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 알케닐 또는 알키닐 탄소 쇄인,
사료 조성물 또는 사료 첨가제.10. A process for the preparation of a compound of formula I according to claim 1, 2 and 4 to 6,
Wherein the organic molecule of formula (I) is a compound of formula (III)
III
In this formula,
n ranges from 0 to 12, with n? 0, the carbon chain may be unsubstituted or substituted with up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups Or an alkenyl or alkynyl carbon chain which is mono-unsaturated or poly-unsaturated and in any isomeric form,
R4 is independently hydrogen or a saturated linear, cyclic or branched chain of an alkyl or alkenyl group containing from 1 to 12 carbon atoms,
X is hydrogen, R5, R5≡N, -OR5, -OCOR5 , -NR5R6, -ONO 2, -COOR5, -CONR5R6, -NHSO 2 R5, or -SO 2 NHR5,
R5 and R6 are independently selected from the group consisting of C 1 to C 12 linear, branched, or cyclic alkyl groups substituted with hydrogen, unsubstituted or up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups. Or a cyclic alkyl chain, or an alkenyl or alkynyl carbon chain which may be mono- or polyunsaturated and in any isomeric form,
Feed composition or feed additive.
무기물 예비배합물, 비타민 예비배합물, 또는 비타민과 무기물을 포함하는 예비배합물, 또는 볼러스(bolus)인 조성물.12. The method of claim 11,
A preliminary combination comprising a mineral pre-combination, a vitamin pre-combination, or a vitamin and an inorganic, or a bolus.
하기 화학식 Ⅰ로 정의되는, 임의의 위치에 하나 이상의 니트로옥시기가 치환된 유기 분자 또는 이의 염 하나 이상을 충분량으로 경구 투여함을 포함하되,
Ⅰ
상기 식에서,
Y는 CaHbOdNeSg의 조성의 유기 분자로서, 이때 a는 1 내지 25 범위이며, b는 2 내지 51 범위이며, d는 0 내지 8 범위이며, e는 0 내지 5 범위이며, g는 0 내지 3 범위이고;
상기 화학식 I의 유기 분자가 하기 화학식 III의 화합물이되,
III
상기 식에서,
n은 0 내지 12 범위이며, 이때 n ≠ 0이면, 탄소 쇄는, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 치환될 수 있는 선형, 환형 또는 분지형 지방족 탄소 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태인 알케닐 또는 알키닐 탄소 쇄이며,
R4는 독립적으로, 수소 또는 1 내지 12개의 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형, 환형 또는 분지형 쇄이며,
X는 수소, R5, R5≡N, -OR5, -OCOR5, -NR5R6, -ONO2, -COOR5, -CONR5R6, -NHSO2R5, 또는 -SO2NHR5이며,
R5 및 R6은 독립적으로, 수소, 비치환되거나 3개 이하의 하이드록실-, 알콕시-, 아미노-, 알킬아미노-, 다이알킬아미노- 또는 니트로옥시 기로 치환된 C1 내지 C12의 선형, 분지형 또는 환형 알킬 쇄, 또는 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 알케닐 또는 알키닐 탄소 쇄이고;
하기 화학식 II로 정의되는 니트로옥시 알칸산 또는 이의 유도체는 제외되고,
II
상기 식에서,
u는 0 내지 23 범위이고, 이때 u ≠ 0이면, 탄소 쇄는, 단일불포화되거나 다중불포화되고 임의의 이성체 형태일 수 있는 선형, 환형, 또는 분지된 선형 또는 환형 지방족 탄소 쇄이며,
Z는 독립적으로, O, NH 또는 N-R3이고, 이때 R1 ≠ H이면, Z-R1-은 에스터 또는 2차 아마이드 유도체를 나타내며,
R1은 독립적으로, 수소 또는 1 내지 10개 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형, 환형 또는 분지형 쇄이며,
R2는 독립적으로, 수소 또는 1 내지 23개 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형 또는 분지형 쇄이며,
R3은 독립적으로, 수소 또는 1 내지 10개 탄소 원자를 포함하는 알킬 또는 알케닐 기의 포화된 선형, 환형 또는 분지형 쇄인, 방법.As a method for reducing / reducing the production of methane from ruminant digestive activity or improving the development of ruminants,
Comprising orally administering to a patient in need thereof one or more organic molecules or at least one salt thereof substituted with at least one nitrooxy group at any position,
Ⅰ
In this formula,
Y is an organic molecule having a composition of C a H b O d N e S g where a ranges from 1 to 25, b ranges from 2 to 51, d ranges from 0 to 8, e ranges from 0 to 5 And g ranges from 0 to 3;
Wherein the organic molecule of formula (I) is a compound of formula (III)
III
In this formula,
n ranges from 0 to 12, with n? 0, the carbon chain may be unsubstituted or substituted with up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups Or an alkenyl or alkynyl carbon chain which is mono-unsaturated or poly-unsaturated and in any isomeric form,
R4 is independently hydrogen or a saturated linear, cyclic or branched chain of an alkyl or alkenyl group containing from 1 to 12 carbon atoms,
X is hydrogen, R5, R5≡N, -OR5, -OCOR5 , -NR5R6, -ONO 2, -COOR5, -CONR5R6, -NHSO 2 R5, or -SO 2 NHR5,
R5 and R6 are independently selected from the group consisting of C 1 to C 12 linear, branched, or cyclic alkyl groups substituted with hydrogen, unsubstituted or up to three hydroxyl-, alkoxy-, amino-, alkylamino-, dialkylamino- or nitrooxy groups. Or a cyclic alkyl chain, or an alkenyl or alkynyl carbon chain which may be mono-unsaturated or poly-unsaturated and in any isomeric form;
A nitrooxyalkanoic acid or derivative thereof defined by the following formula (II) is excluded,
II
In this formula,
u ranges from 0 to 23, where u ≠ 0, the carbon chain is a linear, cyclic, or branched linear or cyclic aliphatic carbon chain, which may be singly or multiply unsaturated and in any isomeric form,
Z is independently O, NH or N-R3, wherein when R1 is not equal to H then Z-R1- represents an ester or secondary amide derivative,
R1 is independently hydrogen or a saturated linear, cyclic or branched chain of an alkyl or alkenyl group containing from 1 to 10 carbon atoms,
R2 is independently a saturated linear or branched chain of hydrogen or an alkyl or alkenyl group containing from 1 to 23 carbon atoms,
R3 is independently a saturated linear, cyclic or branched chain of hydrogen or an alkyl or alkenyl group containing from 1 to 10 carbon atoms.
하나 이상의 상기 유기 분자가, 다이알릴 다이설파이드, 마늘 기름, 알릴 아이소티오시아네이트, 데옥시콜산, 케노데옥시콜산 및 이들의 유도체로 구성된 군으로부터 선택된 하나 이상의 추가 활성 물질과 조합되어 동물에게 투여되는, 방법.14. The method of claim 13,
Wherein the at least one organic molecule is administered to an animal in combination with one or more additional active substances selected from the group consisting of diallyl disulfide, garlic oil, allyl isothiocyanate, deoxycholic acid, chenodeoxycholic acid, and derivatives thereof , Way.
상기 반추동물이 소, 염소, 양, 기린, 미국 들소, 유럽 들소, 야크, 물소, 사슴, 낙타, 알파카, 라마, 누, 영양, 가지뿔영양, 및 닐가이 영양으로 구성된 군으로부터 선택된, 방법.The method according to claim 13 or 14,
Wherein said ruminant is selected from the group consisting of cattle, goats, sheep, giraffes, american bison, European bison, yak, buffalo, deer, camel, alpaca, llama, nu, nutrition, eggplant horn nutrition, and neem nutrition.
반추동물에게 투여되는 하나 이상의 상기 화학식 I로 정의된 유기 분자의 양이 사료(㎏) 당 1 ㎎ 내지 10 g인, 방법.The method according to claim 13 or 14,
Wherein the amount of at least one of the organic molecules defined in formula I administered to the ruminant is between 1 mg and 10 g per kilogram of feed.
건조 물질 섭취량(㎏) 당 리터(ℓ)로 계산된 반추동물에서의 메탄 생산량이 대사 챔버에서 측정시 10% 이상 감소되는, 방법.The method according to claim 13 or 14,
Wherein the methane production in the ruminant calculated as liters per liter of dry substance intake (kg) is reduced by at least 10% when measured in the metabolic chamber.
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